5-Substituted isoquinoline derivatives

ABSTRACT

A compound represented by the following formula (1) or a salt thereof:  
                 
 
wherein R 1  represents hydrogen atom, a halogen atom and the like; R 2  represents hydrogen atom, a halogen atom, a C 1-6  alkyl group and the like; and R 3  represents —O—X—C(A 1 )(A 11 )—C(A 2 )(A 2l )—N(A 3l )(A 3 )(X represents propylene group etc., A 11  and A 21  represent hydrogen atom, or a C 1-6  alkyl group, A 31  represents a C 1-6  alkyl group substituted with hydroxyl group, or hydrogen atom, and A 1 , A 2 , and A 3  represent hydrogen atom, a C 1-6  alkyl group and the like) and the like, which has an inhibitory activity on the phosphorylation of myosin regulatory light chain, and is useful for treatment of diseases relating to contraction of various cells and the like.

TECHNICAL FIELD

The present invention relates to a novel 5-substituted isoquinolinederivative or a salt thereof, and a medicament comprising said5-substituted isoquinoline derivative or a salt thereof as an activeingredient.

BACKGROUND ART

Movements of cells includes contraction, migration, release, aggregationand the like, and phosphorylation of the myosin regulatory light chainis important for these cell movements. The myosin regulatory light chainis a subunit having a molecular weight of 20 kDa and constitutingmyosin, which exists in smooth muscle cells and various non-muscle cellssuch as neutrophils, leukocytes, platelets and nerve cells ofwarm-blooded animals (Barany, K., et al., Biochemistry of Smooth MuscleContraction, pp.21-35, 1996). Myosin existing in smooth muscle cells andvarious non-muscle cells such as neutrophils, leukocytes, platelets andnerve cells of warm-blooded animals is constituted by a myosin heavychain subunit having a molecular weight of about 200 kDa, the myosinregulatory light chain subunit having a molecular weight of about 20kDa, and a myosin constitutive light chain subunit having a molecularweight of about 17 kDa. The myosin regulatory light chain is mainlyphosphorylated by the myosin light chain kinase to increase the activityof myosin ATPase existing in the myosin heavy chain subunit (Barany, M.,et al., Biochemistry of Smooth Muscle Contraction, pp.321-339, 1996). Itis known that the activated myosin having the increased ATPase activitybecomes possible to interact with actin and activates movementapparatuses of cytoskeleton to activate cell movements.

That is, it is known that activation of myosin relates to cellcontraction (Kamm, K., et al., Annu. Rev. Physiol., 51, pp.299-313,1989). It is also known that activation of myosin relates to change ofcell morphology (Schmidt, J. T. et al., J, Neurobiol., 52 (3),pp.175-188, 2002). It is known that activation of myosin relates to cellmigration (Niggli, V., FEBS Lett., 445, pp.69-72, 1999), and it is alsoknown that activation of myosin relates to cell release (Kitani, S., etal., Biochem. Biophys. Res. Commun., 183, pp.48-54, 1992). It is furtherknown that activation of myosin relates to cell aggregation (Itoh, K.,et al., Biochim. Biophys. Acta., 1136, pp.52-56, 1992), and it is alsoknown that activation of myosin relates to cell apoptosis (Mills, J. C.et al., J. Cell Biol., Vol. 140, No. 3, pp.627-636, 1998).

Based on these findings, it is considered that an agent which inhibitsthe phosphorylation of the myosin regulatory light chain suppresses cellcontraction, regulates change of cell morphology, suppresses cellmigration, suppresses cell release, suppresses cell aggregation andsuppresses cell apoptosis.

Cell contraction is deeply involved in diseases relating to contractionof various smooth muscle layers. Examples of such diseases include, forexample, hypertension (A. P. Samlyo et al., Rev. Physiol. Biochem.Pharmacol., Vol. 134, pp.209-34, 1999), angina pectoris (Shimokawa etal., Cardiovasc. Res., Vol. 43, No. 4, pp.1029-39, 1999; Satoh, H., etal., Jpn. J. Pharmacol., 79 (suppl.), p.211, 1999), cerebral vascularspasm (M. Satoh et al., the 57th General Meeting of Japan NeurosurgicalSociety, Collection of Abstracts, 153, 1998; N. Ono et al., Pharmacol.Ther., Vol. 82, No. 2-3, pp.123-31, 1991; Shimokawa et al., Cardiovasc.Res., Vol. 43, No. 4, pp.1029-39, 1999), erectile dysfunction(Andersson, K E. et al., World J. Vrol., 15, pp.14-20, 1997), bronchialasthma (K. Iidzuka, Allergy, 47, 943, 1998; K. Iidzuka et al., Jpn. J.Respirology Society, 37, 196, 1999) and the like.

Change of cell morphology is deeply involved in diseases relating tomorphological change of various cells. Examples of the diseases relatingto change of cell morphology include, for example, various nervedysfunctions as those relating to nerve cells. As the nervedysfunctions, for example, neural damages caused by trauma,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and diabetic retinopathy and the like can be exemplified(Arakawa, Y., et al., BIO Clinica, 17 (13), pp.26-28, 2002).

Cell migration is deeply involved in diseases relating to migration ofvarious cells. Examples of such diseases include, for example, cancerinvasion and metastasis (Itoh, K. et al., Nat. Med., Vol. 5, No. 2,pp.221-5, 1999; Keely, P. et al., Trends Cell Biol., Vol. 8, No. 3,pp.101-6, 1998), nephritis (Fujimoto, O. et al., Journal of JapaneseSociety of Internal Medicine, 88 (1), pp.148-58, 1998) and the like.

Furthermore, it is considered that cell release is deeply involved invarious allergies and the like (Keane-Myers A. et al., Curr. AllergyAsthma Rep., 1(6):550-557, 2001), and cell aggregation is considered tobe deeply involved in thrombosis and the like (Nakai, K. et al., Blood,Vol. 90, No. 10, pp.3736-42., 1997). Further, it is known that cellapoptosis is involved in neurodegenerative diseases such as Alzheimer'sdisease and Parkinson's disease, viral diseases, hepatic diseases andthe like (Thompson, C. B., Science, Vol. 267, pp.1456-1462, 1995).

Based on these findings, it is considered that the inhibitor of thephosphorylation of myosin regulatory light chain of the presentinvention, which is an agent inhibiting the phosphorylation of themyosin regulatory light chain, is useful as an active ingredient of amedicament for prophylactic and/or therapeutic treatment of a diseaserelating to cell contraction, disease relating to change of cellmorphology, disease relating to cell migration, disease relating to cellrelease, disease relating to cell aggregation, and/or disease relatingto cell apoptosis.

It has been reported that 1-(5-isoquinolinesulfonyl)-2-methylpiperazine(H-7), which is an isoquinoline derivative, inhibits phosphorylation ofthe myosin regulatory light chain of mesenteric artery (Suzuki, A. etal., Br. J. Pharmacol., 109, pp.703-712, 1993), iris smooth muscle cell(Howe, P. H. et al., Biochem J., 255, pp.423-429, 1988), and astrocyte(Mobley P. L., et al., Exp. Cell Res., 214, pp.55-66, 1994).

DISCLOSURE OF THE INVENTION

Conventionally, it has been desired to provide a novel compound havingan action of strongly inhibiting the phosphorylation of myosinregulatory light chain.

The inventors of the present invention direct their attentions to thephysiological functions of isoquinoline derivatives, and synthesizedvarious isoquinoline derivatives and studied pharmacological actionsthereof. As a result, it was found that the compounds represented by thefollowing formula (1) and salts thereof had the desired pharmacologicalaction, and were useful as an active ingredient of a medicament forprophylactic and/or therapeutic treatment of diseases relating to cellcontraction, those relating to change of cell morphology, those relatingto cell migration, those relating to cell release, those relating tocell aggregation, and those relating to cell apoptosis. The presentinvention was achieved on the basis of these findings.

The present invention thus provides a compound represented by thefollowing formula (1) or a salt thereof:

wherein R¹ represents hydrogen atom, a halogen atom, hydroxyl group,amino group, or a C₁₋₆ alkoxyl group;

-   -   R² represents hydrogen atom, a halogen atom, a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), —(C₂₋₃ alkylene)CO₂(G¹), —N(G²)(G³),        —O(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃        alkylene)N(G²)(G³), a C₂₋₃ alkenyl group, a C₂₋₃ alkynyl group,        a C₁₋₆ alkoxyl group, —(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl),        —S(O)_(p)(C₁₋₆ alkyl), —O(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl), or        cyano group;    -   G¹, G², and G³ independently represent hydrogen atom, or a C₁₋₆        alkyl group;    -   p represents an integer of from 0 to 2;    -   R³ represents a group represented by the following formula        (1-1), formula (1-2), or formula (1-3);        wherein

-   (i) when R³ represents a group represented by the formula (1-1):    -   X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond;    -   A¹¹, A²¹, A⁵¹, and A⁶¹ independently represent hydrogen atom, or        a C₁₋₆ alkyl group;    -   A³¹ represents a C₁₋₆ alkyl group substituted with hydroxyl        group, or hydrogen atom; and    -   groups in each of one or more combinations selected from the        group consisting of combinations of A³ and A², A³ and A¹, A³ and        A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹        and A⁶, and A⁵ and A⁶ bind to each other to form a 5- or        6-membered ring, provided that a group or groups among A¹, A²,        A³, A⁵, and A⁶ not involved in the ring formation independently        represent hydrogen atom, or a C₁₋₆ alkyl group;

-   (ii) when R³ represents a group represented by the formula (1-2):    -   X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond;    -   A¹¹, A²¹, A⁵¹, and A⁶¹ independently represent hydrogen atom, or        a C₁₋₆ alkyl group;    -   A³¹ represents a C₁₋₆ alkyl group substituted with hydroxyl        group, or hydrogen atom;    -   R⁴ represents hydrogen atom, or a C₁₋₆ alkyl group; and    -   A¹, A², A³, A⁵, and A⁶ independently represent hydrogen atom, or        a C₁₋₆ alkyl group; or    -   groups in each of one or more combinations selected from the        group consisting of combinations of A³ and A², A³ and A¹, A³ and        A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹        and A⁶, and A⁵ and A⁶ may bind to each other to form a 5- or        6-membered ring; or

-   (iii) when R³ represents a group represented by the formula (1-3):    -   Y represents a C₂₋₆ alkylene group, a C₂₋₆ alkylene group        substituted with a C₁₋₆ alkyl group, a C₂₋₆ alkylene group        substituted with phenyl group, a C₂₋₆ alkylene group substituted        with benzyl group, —(C₁₋₆ alkylene)phenylene(C₁₋₆ alkylene)—,        1,2-cyclohexylene group, or 1,3-cyclohexylene group;    -   A⁴ represents hydrogen atom, or a C₁₋₆ alkyl group, or may binds        to any one of carbon atoms of the alkylene moiety of Y to form a        4- to 7-membered ring;    -   R⁵ represents —(C₂₋₆ alkylene)(cycloalkyl), —(C₂₋₆        alkylene)(aryl), —(C₂₋₆ alkylene)(heteroaryl), —(C₂₋₆        alkylene)S(O)_(q)(cycloalkyl), —(C₂₋₆ alkylene)S(O)_(q)(aryl),        —(C₂₋₆ alkylene)S(O)_(q)(heteroaryl), —(C₂₋₆        alkylene)N(G⁶)(cycloalkyl), —(C₂₋₆ alkylene)N(G⁶)(aryl), —(C₂₋₆        alkylene)N(G⁶)(heteroaryl), —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl),        —(C₂₋₆ alkylene)CON(G⁶)(aryl), or —(C₂₋₆        alkylene)CON(G⁶)(heteroaryl);    -   G⁶ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   q represents an integer of from 0 to 2;    -   said “aryl” is a phenyl group which may be substituted with one        or more substituents selected from the group consisting of a        halogen atom, a C₁₋₆ alkyl group, CF₃ group, a C₁₋₆ alkoxyl        group, cyano group, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and        —N(G⁹)SO₂(C₁₋₆ alkyl);    -   G⁹ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   G⁷ and G⁸ independently represents hydrogen atom, or a C₁₋₆        alkyl group, or —N(G⁷)(G⁸) in the (aryl) as a whole may form a        4- to 7-membered ring which may contain oxygen atom, sulfur        atom, or an N(G¹⁰) group, besides said nitrogen atom;    -   G¹⁰ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   said “heteroaryl” is selected from pyranyl, pyrazinyl, dioxolyl,        furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl,        pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl,        and these groups may be substituted with one or more        substituents selected from the group consisting of a C₁₋₆ alkyl        group which may optionally be substituted with a halogen atom,        and a halogen atom; and    -   r represents an integer of from 0 to 2.

The present invention also provides a compound represented by theaforementioned formula (1) or a salt thereof, wherein

-   -   R¹ represents hydrogen atom, a halogen atom, hydroxyl group,        amino group, or a C₁₋₆ alkoxyl group;    -   R² represents hydrogen atom, a halogen atom, a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), —(C₂₋₃ alkylene)CO₂(G¹), —N(G²)(G³),        —O(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃        alkylene)N(G²)(G³), a C₂₋₃ alkenyl group, a C₂₋₃ alkynyl group,        a C₁₋₆ alkoxyl group, —(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl),        —S(O)_(p)(C₁₋₆ alkyl), or —O(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl);    -   G¹, G², and G³ independently represent hydrogen atom, or a C₁₋₆        alkyl group;    -   p represents an integer of from 0 to 2;    -   R³ represents a group represented by the formula (1-1), formula        (1-2), or formula (1-3);        wherein

-   (i) when R³ represents a group represented by the formula (1-1):    -   X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,        C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond;    -   A¹¹, A²¹, A⁵¹, and A⁶¹ independently represent hydrogen atom, or        a C₁₋₆ alkyl group;    -   A³¹ represents hydrogen atom; and    -   groups in each of one or more combinations selected from the        group consisting of combinations of A³ and A², A³ and A¹, A³ and        A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹        and A⁶, and A⁵ and A⁶ bind to each other to form a 5- or        6-membered ring, provided that a group or groups among A¹, A²,        A³, A⁵, and A⁶ not involved in the ring formation independently        represent hydrogen atom, or a C₁₋₆ alkyl group;

-   (ii) when R³ represents a group represented by the formula (1-2):    -   X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond;    -   A¹¹, A²¹, A⁵¹, and A⁶¹ independently represent hydrogen atom, or        a C₁₋₆ alkyl group;    -   A³¹ represents hydrogen atom;    -   R⁴ represents hydrogen atom, or a C₁₋₆ alkyl group; and    -   A¹, A², A³, A⁵, and A⁶ independently represent hydrogen atom, or        a C₁₋₆ alkyl group; or    -   groups in each of one or more combinations selected from the        group consisting of combinations of A³ and A², A³ and A¹, A³ and        A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹        and A⁶, and A⁵ and A⁶ may bind to each other to form a 5- or        6-membered ring; or

-   (iii) when R³ represents a group represented by the formula (1-3):    -   Y represents a C₂₋₆ alkylene group, a C₂₋₆ alkylene group        substituted with a C₁₋₆ alkyl group, a C₂₋₆ alkylene group        substituted with phenyl group, a C₂₋₆ alkylene group substituted        with benzyl group, —(C₁₋₆ alkylene)phenylene(C₁₋₆ alkylene)—,        1,2-cyclohexylene group, or 1,3-cyclohexylene group;    -   A⁴ represents hydrogen atom, or a C₁₋₆ alkyl group, or may binds        to any one of carbon atoms of the alkylene moiety of Y to form a        4- to 7-membered ring;    -   R⁵ represents —(C₂₋₆ alkylene)(cycloalkyl), —(C₂₋₆        alkylene)(aryl), —(C₂₋₆ alkylene)(heteroaryl), —(C₂₋₆        alkylene)S(O)_(q)(cycloalkyl), —(C₂₋₆ alkylene)S(O)_(q)(aryl),        —(C₂₋₆ alkylene)S(O)_(q)(heteroaryl), —(C₂₋₆        alkylene)N(G⁶)(cycloalkyl), —(C₂₋₆ alkylene)N(G⁶)(aryl), —(C₂₋₆        alkylene)N(G⁶)(heteroaryl), —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl),        —(C₂₋₆ alkylene)CON(G⁶)(aryl), or —(C₂₋₆        alkylene)CON(G⁶)(heteroaryl);    -   G⁶ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   q represents an integer of from 0 to 2;    -   said “aryl” is a phenyl group which may be substituted with one        or more substituents selected from the group consisting of a        halogen atom, a C₁₋₆ alkyl group, CF₃ group, a C₁₋₆ alkoxyl        group, cyano group, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and        —N(G⁹)SO₂(C₁₋₆ alkyl);    -   G⁹ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   G⁷ and G⁸ independently represents hydrogen atom, or a C₁₋₆        alkyl group, or —N(G⁷)(G⁸) in the (aryl) as a whole may form a        4- to 7-membered ring which may contain oxygen atom, sulfur        atom, or an N(G¹⁰) group, besides said nitrogen atom;    -   G¹⁰ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   said “heteroaryl” is selected from pyranyl, pyrazinyl, dioxolyl,        furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl,        pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl,        and these groups may be substituted with one or more        substituents selected from the group consisting of a C₁₋₆ alkyl        group which may optionally be substituted with a halogen atom,        and a halogen atom; and    -   r represents an integer of from 0 to 2.

The present invention further provides a compound represented by theaforementioned formula (1) or a salt thereof, wherein

-   -   R¹ represents hydrogen atom, a halogen atom, hydroxyl group,        amino group, or a C₁₋₆ alkoxyl group;    -   R² represents hydrogen atom, a halogen atom, a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), —(C₂₋₃ alkylene)CO₂(G¹), —N(G²)(G³),        —O(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃        alkylene)N(G²)(G³), a C₂₋₃ alkenyl group, a C₂₋₃ alkynyl group,        a C₁₋₆ alkoxyl group, —(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl),        —S(O)_(p)(C₁₋₆ alkyl), or —O(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl);    -   G¹, G², and G³ independently represent hydrogen atom, or a C₁₋₆        alkyl group;    -   p represents an integer of from 0 to 2;    -   R³ represents a group represented by the formula (1-1), formula        (1-2), or formula (1-3);        wherein    -   A¹, A¹¹, A², and A²¹ independently represent hydrogen atom, or a        C₁₋₆ alkyl group;    -   A³ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   A³¹ represents hydrogen atom;    -   X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond;    -   A⁵, A⁵¹, A⁶, and A⁶¹ independently represent hydrogen atom, or a        C₁₋₆ alkyl group;    -   alkyl groups represented by two of groups included in one or        more combinations selected from the group consisting of        combinations of A³ and A², A³ and A¹, A³ and A⁵, A³ and A⁶, A²        and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ and A⁶, and A⁵ and        A⁶ may bind to each other to form a 5- or 6-membered ring;    -   R⁴ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   Y represents a C₂₋₆ alkylene group, a C₂₋₆ alkylene group        substituted with a C₁₋₆ alkyl group, a C₂₋₆ alkylene group        substituted with phenyl group, a C₂₋₆ alkylene group substituted        with benzyl group, —(C₁₋₆ alkylene)phenylene(C₁₋₆ alkylene)—,        1,2-cyclohexylene group, or 1,3-cyclohexylene group;    -   A⁴ represents hydrogen atom, or a C₁₋₆ alkyl group, or may binds        to any one of carbon atoms of the alkylene moiety of Y to form a        4- to 7-membered ring;    -   R⁵ represents —(C₂₋₆ alkylene)(cycloalkyl), —(C₂₋₆        alkylene)(aryl), —(C₂₋₆ alkylene)(heteroaryl), —(C₂₋₆        alkylene)S(O)_(q)(cycloalkyl), —(C₂₋₆ alkylene)S(O)_(q)(aryl),        —(C₂₋₆ alkylene)S(O)_(q)(heteroaryl), —(C₂₋₆        alkylene)N(G⁶)(cycloalkyl), —(C₂₋₆ alkylene)N(G⁶)(aryl), —(C₂₋₆        alkylene)N(G⁶)(heteroaryl), —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl),        —(C₂₋₆ alkylene)CON(G⁶)(aryl), or —(C₂₋₆        alkylene)CON(G⁶)(heteroaryl);    -   G⁶ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   q represents an integer of from 0 to 2;    -   said “aryl” is a phenyl group which may be substituted with one        or more substituents selected from the group consisting of a        halogen atom, a C₁₋₆ alkyl group, CF₃ group, a C₁₋₆ alkoxyl        group, cyano group, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and        —N(G⁹)SO₂(C₁₋₆ alkyl);    -   G⁹ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   G⁷ and G⁸ independently represents hydrogen atom, or a C₁₋₆        alkyl group, or —N(G⁷)(G⁸) in said “aryl” as a whole may form a        4- to 7-membered ring which may contain oxygen atom, sulfur        atom, or an N(G¹⁰) group, besides said nitrogen atom;    -   G¹⁰ represents hydrogen atom, or a C₁₋₆ alkyl group;    -   said “heteroaryl” is selected from pyranyl, pyrazinyl, dioxolyl,        furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl,        pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl,        and these groups may optionally be substituted with one or more        substituents selected from the group consisting of a C₁₋₆ alkyl        group which may be substituted with a halogen atom, and a        halogen atom; and    -   r represents an integer of from 0 to 2, provided that, when R¹        and R² are hydrogen atoms, and R³ is a group represented by the        formula (1-1), A³ is not hydrogen atom or a C₁₋₆ alkyl group,        and the alkyl groups represented by two of groups included in        one or more combinations selected from the group consisting of        combinations of A³ and A², A³ and A¹, A³ and A⁵, and A³ and A⁶        bind to each other to form a 5- or 6-membered ring.

From another aspect, the present invention provides a medicamentcontaining a compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient. Theaforementioned medicament has an inhibitory action on phosphorylation ofmyosin regulatory light chain, and is useful as a medicament forprophylactic and/or therapeutic treatment of, for example, a diseaserelating to cell contraction, disease relating to change of cellmorphology, disease relating to cell migration, disease relating to cellrelease, disease relating to cell aggregation, and/or disease relatingto cell apoptosis, and the like.

More specifically, there are provided a medicament for decreasingphosphorylation amount of myosin regulatory light chain in a cell, whichcomprises a compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having a cell contraction inhibitory action, which comprisesa compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having an action to regulate change of cell morphology, whichcomprises a compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having a cell migration inhibitory action, which comprises acompound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having a cell release inhibitory action, which comprises acompound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having a cell aggregation inhibitory action, which comprisesa compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, amedicament having a cell apoptosis inhibitory action, which comprises acompound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient, and amedicament for inhibiting the Rho/Rho kinase pathway, which comprises acompound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof as an active ingredient.

The present invention also provides an inhibitor of the phosphorylationof myosin regulatory light chain containing a compound represented bythe aforementioned formula (1) or a physiologically acceptable saltthereof, and an inhibitor of the Rho/Rho kinase pathway comprising acompound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof.

From another aspect, the present invention provides use of a compoundrepresented by the aforementioned formula (1) or a physiologicallyacceptable salt thereof for manufacture of the aforementionedmedicaments. The present invention also provides a method forprophylactic and/or therapeutic treatment of a disease relating to cellcontraction, disease relating to change of cell morphology, diseaserelating to cell migration, disease relating to cell release, diseaserelating to cell aggregation, and/or disease relating to cell apoptosisand the like, which comprises the step of administrating aprophylactically and/or therapeutically effective amount of a compoundrepresented by the aforementioned formula (1) or a physiologicallyacceptable salt thereof to a mammal including human, a method fordecreasing phosphorylation amount of myosin regulatory light chain in acell, which comprises the step of administrating an effective amount ofa compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof to a mammal including human, amethod for inhibiting cell contraction, which comprises the step ofadministrating an effective amount of a compound represented by theaforementioned formula (1) or a physiologically acceptable salt thereofto a mammal including human, a method for regulating change of cellmorphology, which comprises the step of administrating an effectiveamount of a compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof to a mammal including human, amethod for inhibiting cell migration, which comprises the step ofadministrating an effective amount of a compound represented by theaforementioned formula (1) or a physiologically acceptable salt thereofto a mammal including human, a method for inhibiting cell release, whichcomprises the step of administrating an effective amount of a compoundrepresented by the aforementioned formula (1) or a physiologicallyacceptable salt thereof to a mammal including human, a method forinhibiting cell aggregation, which comprises the step of administratingan effective amount of a compound represented by the aforementionedformula (1) or a physiologically acceptable salt thereof to a mammalincluding human, a method for inhibiting cell apoptosis, which comprisesthe step of administrating an effective amount of a compound representedby the aforementioned formula (1) or a physiologically acceptable saltthereof to a mammal including human, and a method for inhibiting theRho/Rho kinase pathway, which comprises the step of administrating aneffective amount of a compound represented by the aforementioned formula(1) or a physiologically acceptable salt thereof to a mammal includinghuman.

BEST MODE FOR CARRYING OUT THE INVENTION

The alkyl mentioned in this specification may be a linear or branchedalkyl, and for example, a C₁₋₆ alkyl include linear and branched alkylshaving 1 to 6 carbon atoms. Specific examples include methyl, ethyl,propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl,2-methylbutyl, hexyl and the like. The C₁₋₆ alkyl groups as R², A³, A⁴,and R⁴ are independently and preferably methyl group or ethyl group. AsR², methyl group is particularly preferred.

The halogen may be any of fluorine atom, chlorine atom, bromine atom,and iodine atom. In particular, the halogen atom as R¹ is preferablychlorine atom, and the halogen atom as R² is preferably fluorine atom,or bromine atom, most preferably fluorine atom.

The alkoxyl group is not particularly limited. For example, a C₁₋₆alkoxyl group includes linear and branched alkoxyl groups having 1 to 6carbon atoms. Specific examples include methoxy group, ethoxy group,propoxy group, isopropoxy group and the like. Preferred examples of thealkoxyl group as R¹ and R² include methoxy group and ethoxy group, andmethoxy group is a particularly preferred example.

R¹ is preferably hydrogen atom, hydroxyl group, or amino group. As R¹,any one, two or more kinds of these groups may be preferably chosen. R¹is preferably hydrogen atom, or hydroxyl group, most preferably hydrogenatom.

R² is preferably hydrogen atom, a halogen atom, a C₁₋₆ alkyl group,—N(G²)(G³), a C₂₋₃ alkenyl group, a C₂₋₃ alkynyl group, a C₁₋₆ alkoxylgroup, or —S(O)_(p)(C₁₋₆ alkyl). Cyano group is also preferred.

R² is still more preferably hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, —N(G²)(G³), or a C₁₋₆ alkoxyl group.

Further, other preferred examples are as follows.

R² is preferably hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, aC₂₋₃ alkenyl group, a C₂₋₃ alkynyl group, or a C₁₋₆ alkoxyl group.

R² is preferably hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxyl group, or —S(O)_(p)(C₁₋₆ alkyl).

R² is preferably hydrogen atom, a halogen atom, or a C₁₋₆ alkyl group,and among these, a combination of hydrogen atom and a halogen atom, anda combination of hydrogen atom and a C₁₋₆ alkyl group are preferredexamples.

R² is preferably a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group. Among thesegroups, preferred examples are combinations of a C₁₋₆ alkyl group, aC₂₋₃ alkenyl group, or cyano group, and combinations of a C₁₋₆ alkylgroup, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, or —S(O)_(p)(C₁₋₆alkyl).

Further, R² is preferably a C₁₋₆ alkyl group, a C₂₋₃ alkenyl group, orcyano group. Preferred examples of the C₁₋₆ alkyl group include methylgroup, preferred examples of the C₂₋₃ alkenyl group include vinyl group,and any one, two or more of them are also preferably chosen.

R² is preferably —(C₂₋₃ alkylene)O(G¹), and more specifically, preferredexamples include hydroxymethyl group, 2-hydroxyethyl group,3-hydroxypropyl group, 2-methoxyethyl group, and 3-methoxypropyl group,and hydroxymethyl group is particularly preferred.

R² is preferably —(C₂₋₃ alkylene)CO₂(G¹), and more specifically,preferred examples include 2-carboxyethyl group, 3-carboxypropyl group,2-methoxycarbonylethyl group, and 3-methoxycarbonylpropyl group.

R² is preferably —N(G²)(G³), and more specifically, preferred examplesinclude amino group, methylamino group, and dimethylamino group.

R² is preferably —O(C₂₋₃ alkylene)O(G¹), and more specifically,preferred examples include 2-hydroxyethoxy group, 3-hydroxypropyloxygroup, 2-methoxyethoxy group, and 3-methoxypropyloxy group.

R² is preferably —NH(C₂₋₃ alkylene)O(G¹), and more specifically,preferred examples include 2-(hydroxyethyl)amino group,3-(hydroxypropyl)amino group, 2-(methoxyethyl)amino group, and3-(methoxypropyl)amino group.

R² is preferably —NH(C₂₋₃ alkylene)N(G²)(G³), and more specifically,preferred examples include 2-aminoethylamino group, 3-aminopropylaminogroup, 2-(methylamino)ethylamino group, 3-(methylamino)propylaminogroup, 2-(dimethylamino)ethylamino group, and3-(dimethylamino)propylamino group.

R² is preferably a C₂₋₃ alkenyl group, and more specifically, preferredexamples include ethenyl group and 2-propenyl group.

R² is preferably a C₂₋₃ alkynyl group, and more specifically, preferredexamples include ethynyl group and 2-propynyl group.

R² is preferably a C₁₋₆ alkoxyl group. More specifically, preferredexamples include methoxy group, ethoxy group, propoxy group, andisopropoxy group, and methoxy group is a particularly preferred example.

R² is preferably —(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl), and more specifically,preferred examples include 2-(methanesulfonyl)ethyl group,3-(methanesulfonyl)propyl group, 2-(ethanesulfonyl)ethyl group, and3-(ethanesulfonyl)propyl group.

R² is preferably —S(O)_(p)(C₁₋₆ alkyl). That is, R² is preferably—S(C₁₋₆ alkyl), —SO(C₁₋₆ alkyl), or —SO₂(C₁₋₆ alkyl). More specifically,—S(C₁₋₆ alkyl) is preferably methylthio group or ethylthio group,—SO(C₁₋₆ alkyl) is preferably methylsulfinyl group or ethylsulfinylgroup, and preferred examples of —SO₂(C₁₋₆ alkyl) includemethanesulfonyl group and ethanesulfonyl group.

R² is preferably —O(C₂₋₃ alkylene)SO₂ (C₁₋₆ alkyl), and morespecifically, preferred examples include 2-(methanesulfonyl)ethoxygroup, 3-(methanesulfonyl)propoxy group, 2-(ethanesulfonyl)ethoxy group,and 3-(ethanesulfonyl)propoxy group.

R³ is preferably a group represented by the formula (1-1), formula(1-2), or formula (1-3). Each of these and combinations of two of theseare also preferred examples. That is, a group represented by the formula(1-1), and group represented by the formula (1-2) are preferredexamples.

A¹¹, A²¹, A⁵¹, and A⁶¹ may be the same or different, and they preferablyrepresent hydrogen atom or a C₁₋₆ alkyl group. Preferred examples of theC₁₋₆ alkyl group include methyl group and ethyl group. It isparticularly preferred that all of A¹¹, A²¹, A⁵¹, and A⁶¹ representhydrogen atom, and it is also preferred that any one of A¹¹, A²¹, A⁵¹,and A⁶¹ is methyl group or ethyl group, and all remaining substituentsare hydrogen atoms.

A³¹ is preferably hydrogen atom.

A³¹ is also preferably a C₁₋₆ alkyl group substituted with hydroxylgroup, and it is usually preferably substituted with one hydroxyl group.A particularly preferred example is a C₁₋₆ alkyl group of which end issubstituted with hydroxyl group, and more specifically, preferredexamples are 2-hydroxyethyl group and 3-hydroxypropyl group.

X is preferably propylene group, butylene group, —C(A⁵)(A⁵¹)—, or—C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, and propylene group, —C(A⁵)(A⁵¹)—, and—C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)— are also preferred. Further, —C(A⁵)(A⁵¹)—, and—C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)— are particularly preferred. Examples of—C(A⁵)(A⁵¹)— include methylene group, and examples of—C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)— include ethylene group.

Further, in the present invention, concerning R³, groups in each of oneor more combinations selected from the group consisting of combinationsof A³ and A², A³ and A¹, A³ and A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A²and A⁶, A¹ and A⁵, A¹ and A⁶, and A⁵ and A⁶ may bind to each other toform a 5- or 6-membered ring, and a 6-membered ring is preferred. It isparticularly preferred that one ring is formed. It is preferred that thering consists of carbon atoms, or when the ring contains a nitrogen atomto which A³ binds, the ring consists of carbon atoms except for thenitrogen atom. The ring is preferably a saturated ring.

Among A¹, A², A³, A⁵, and A⁶, the group or groups not involved in thering formation independently represent hydrogen atom, or a C₁₋₆ alkylgroup, and preferred examples of the C₁₋₆ alkyl group include methylgroup and ethyl group. It is particularly preferred that all of A¹, A²,A³, A⁵, and A⁶ represent hydrogen atom, and it is also preferred thatany one of A¹, A², A³, A⁵, and A⁶ is methyl group or ethyl group, andall remaining substituents are hydrogen atoms.

Further, when a ring is formed by any of combinations of A¹ and A³, A²and A³, A³ and A⁵, and A² and A⁵, A¹¹, A², and A²¹ most preferablyrepresent hydrogen atom.

Specifically, examples of the whole structure of the group representedby the formula (1-1), in which a ring is formed by any of theaforementioned combinations, include the following rings.

Among them, groups represented by the formula (1-1-4), formula (1-1-5),formula (1-1-6), and formula (1-1-7) are preferred, and groupsrepresented by the formula (1-1-4), and formula (1-1-7) are morepreferred. Further, groups represented by the formula (1-1-7) arementioned as preferred examples.

Further, examples of the whole structure of the group represented by theformula (1-2), in which a ring is formed by any of the aforementionedcombinations, include the following rings.

Among them, groups represented by the formula (1-2-4), formula (1-2-5),formula (1-2-6), and formula (1-2-7) are preferred, and groupsrepresented by the formula (1-2-4), and formula (1-2-7) are morepreferred. Further, groups represented by the formula (1-2-7) arementioned as preferred examples.

R⁴ is preferably hydrogen atom, or a C₁₋₆ alkyl group, and hydrogen atomis more preferred.

Y is preferably a C₂₋₆ alkylene group, or a C₂₋₆ alkylene groupsubstituted with a C₁₋₆ alkyl group. Preferred examples of the C₂₋₆alkylene group include ethylene group, 1,3-propylene group, and1,4-butylene group. Preferred examples of the C₂₋₆ alkylene groupsubstituted with a C₁₋₆ alkyl group include 1,2-propylene group, and1,3-butylene group.

Examples of the C₂₋₆ alkylene group substituted with phenyl group as Yinclude 1-(phenyl)ethylene, and 2-(phenyl)propylene.

Preferred examples of the C₂₋₆ alkylene group substituted with benzylgroup as Y include 1-(benzyl)ethylene, and 2-(benzyl)propylene.

—(C₁₋₆ alkylene)phenylene(C₁₋₆ alkylene)— as Y is preferably1,3-xylylene group, or 1,4-xylylene group.

Y is preferably 1,3-cyclohexylene.

A⁴ is preferably hydrogen atom, or a C₁₋₆ alkyl group. Preferredexamples of the C₁₋₆ alkyl group include methyl group, and ethyl group.A particularly preferred example of A⁴ is hydrogen atom.

Besides the above, A⁴ may bind to any carbon in the alkylene moiety of Yto form a 4- to 7-membered ring. Specifically, examples of the wholestructure of the group represented by the formula (1-3) in which a ringis formed by any of the aforementioned combinations include thefollowing rings.

Among them, a group represented by the formula (1-3-1) is preferred.

R⁵ is preferably —(C₂₋₆ alkylene)(cycloalkyl), —(C₂₋₆ alkylene)(aryl),—(C₂₋₆ alkylene)(heteroaryl), —(C₂₋₆ alkylene)S(O)_(p)(cycloalkyl),—(C₂₋₆ alkylene)S(O)_(p)(aryl), or —(C₂₋₆ alkylene)S(O)_(p)(heteroaryl).

R⁵ is preferably —(C₂₋₆ alkylene)(aryl), —(C₂₋₆ alkylene)(heteroaryl),—(C₂₋₆ alkylene)S(O)_(p)(aryl), or —(C₂₋₆ alkylene)S(O)_(p)(heteroaryl).

R⁵ is preferably —(C₂₋₄ alkylene)(aryl), —(C₂₋₄ alkylene)(heteroaryl),—(C₂₋₄ alkylene)S(O)_(p)(aryl), or —(C₂₋₄ alkylene)S(O)_(p)(heteroaryl).

R⁵ is preferably —(C₂₋₄ alkylene)(aryl), or —(C₂₋₄alkylene)S(O)_(p)(aryl).

R⁵ is preferably —(C₂₋₄ alkylene)(aryl), —(C₂₋₄ alkylene)(heteroaryl),—(C₂₋₄ alkylene)S(aryl), —(C₂₋₄ alkylene)S(heteroaryl), —(C₂₋₄alkylene)SO₂(aryl), or —(C₂₋₄ alkylene)SO₂(heteroaryl).

R⁵ is preferably —(C₂₋₄ alkylene)(aryl), —(C₂₋₄ alkylene)S(aryl), or—(C₂₋₄ alkylene)SO₂(aryl).

—(C₂₋₆ alkylene)(cycloalkyl) as R⁵ is preferably 2-(cyclopentyl)ethylgroup, 3-(cyclopentyl)propyl group, 2-(cyclohexyl)ethyl group, or3-(cyclohexyl)propyl group.

—(C₂₋₆ alkylene)(aryl) as R⁵ is preferably a 2-(aryl)ethyl group, a3-(aryl)propyl group, or a 4-(aryl)butyl group. The aryl has the meaningas described below.

—(C₂₋₆ alkylene)(heteroaryl) as R⁵ is preferably a 2-(heteroaryl)ethylgroup, a 3-(heteroaryl)propyl group, or a 4-(heteroaryl)butyl group. Theheteroaryl has the meaning as described below.

Preferred examples of —(C₂₋₆ alkylene)S(O)_(p)(cycloalkyl) as R⁵ include2-(cyclopentylthio)ethyl group, a 2-(cyclohexylthio)ethyl group,2-(cyclopentylsulfonyl)ethyl group, and 2-(cyclohexylsulfonyl)ethylgroup. The cycloalkyl has the meaning as described below.

—(C₂₋₆ alkylene)S(O)_(p)(aryl) as R⁵ is preferably a 2-(arylthio)ethylgroup, or a 2-(arylsulfonyl)ethyl group.

—(C₂₋₆ alkylene)S(O)_(p)(heteroaryl) as R⁵ is preferably a2-(heteroarylthio)ethyl group or a 2-(heteroarylsulfonyl)ethyl group.

R⁵ is preferably —(C₂₋₆ alkylene)N(G⁶)(cycloalkyl), —(C₂₋₆alkylene)N(G⁶)(aryl), or —(C₂₋₆ alkylene)N(G⁶)(heteroaryl).

R⁵ is preferably —(C₂₋₆ alkylene)N(G⁶)(cycloalkyl), and morespecifically, preferred examples include 2-(cyclopentylamino)ethylgroup, 2-(cyclohexylamino)ethyl group,2-(N-cyclopentyl-N-methylamino)ethyl group, and2-(N-cyclohexyl-N-methylamino)ethyl group.

R⁵ is preferably —(C₂₋₆ alkylene)N(G⁶)(aryl), and more specifically,preferred examples include a 2-(arylamino)ethyl group and a2-(N-aryl-N-methylamino)ethyl group.

R⁵ is preferably —(C₂₋₆ alkylene)N(G⁶)(heteroaryl), and morespecifically, preferred examples include a 2-(heteroarylamino)ethylgroup and a 2-(N-heteroaryl-N-methylamino)ethyl group.

R⁵ is preferably —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl), —(C₂₋₆alkylene)CON(G⁶)(aryl), or —(C₂₋₆ alkylene)CON(G⁶)(heteroaryl).

R⁵ is preferably —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl), and morespecifically, preferred examples include2-(cyclopentylaminocarbonyl)ethyl group,2-(cyclohexylaminocarbonyl)ethyl group,2-(N-cyclopentyl-N-methylaminocarbonyl)ethyl group, and2-(N-cyclohexyl-N-methylaminocarbonyl)ethyl group .

R⁵ is preferably —(C₂₋₆ alkylene)CON(G⁶)(aryl), and more specifically,preferred examples include a 2-(arylaminocarbonyl)ethyl group, and a2-(N-aryl-N-methylaminocarbonyl)ethyl group.

R⁵ is preferably —(C₂₋₆ alkylene)CON(G⁶)(heteroaryl), and morespecifically, preferred examples include a2-(heteroarylaminocarbonyl)ethyl group, and a2-(N-heteroaryl-N-methylaminocarbonyl)ethyl group.

The aryl as R⁵ is preferably phenyl group, and a substituted phenylgroup is also preferred.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more substituents, most preferably one substituent, selectedfrom the group consisting a halogen atom, a C₁₋₆ alkyl group, CF₃ group,a C₁₋₆ alkoxyl group, cyano group, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹),and —N(G⁹)S(O)₂(C₁₋₆ alkyl).

The substituted phenyl group is preferably a phenyl group substitutedwith one or more substituents, most preferably one substituent, selectedfrom the group consisting a halogen atom, a C₁₋₆ alkyl group, CF₃ group,a C₁₋₆ alkoxyl group, and cyano group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more substituents, most preferably one substituent, selectedfrom the group consisting —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and—N(G⁹)S(O)₂(C₁₋₆ alkyl).

The substituted phenyl group is preferably a phenyl group substitutedwith one or more halogen atoms, most preferably one halogen atom, andthe halogen atoms most preferably consist of fluorine atom, chlorineatom, or bromine atom.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more C₁₋₆ alkyl groups, most preferably one C₁₋₆ alkylgroup, and the C₁₋₆ alkyl group is most preferably methyl group, ethylgroup, propyl group, or isopropyl group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more CF₃ groups, most preferably one CF₃ group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more C₁₋₆ alkoxyl groups, most preferably one C₁₋₆ alkoxylgroup. The C₁₋₆ alkoxyl groups are most preferably consists of methoxygroup or ethoxy group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more cyano groups, most preferably one cyano group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —N(G⁷)(G⁸), most preferably one of —N(G⁷)(G⁸). —N(G⁷)(G⁸) most preferably consists of amino group, methylamino group,dimethylamino group, or ethylamino group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —CO₂(G⁹), most preferably one of —CO₂(G⁹). —CO₂(G⁹)most preferably consists of carboxyl group, methoxycarbonyl group, orethoxycarbonyl group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —S(O)_(r)(G⁹), most preferably one of —S(O)_(r)(G⁹).—S(O)_(r)(G⁹) most preferably consists of methylthio group, ethylthiogroup, methylsulfinyl group, ethylsulfinyl group, methanesulfonyl group,or ethanesulfonyl group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —S(G⁹). —S(G⁹) most preferably consists ofmethylthio group, or ethylthio group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —SO(G⁹). —SO(G⁹) most preferably consists ofmethylsulfinyl group, or ethylsulfinyl group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —SO₂(G⁹). —SO₂(G⁹) is most preferably methylsulfonylgroup, or ethylsulfonyl group.

The substituted phenyl group is preferably a phenyl group substitutedwith one or more of —N(G⁹)SO₂(C₁₋₆ alkyl). —N(G⁹)SO₂(C₁₋₆ alkyl) mostpreferably consists of methanesulfonylamino group, orethanesulfonylamino group.

Preferred examples of the heteroaryl as R⁵ include the followings:pyranyl group; pyrazinyl group; dioxolyl group; furyl group; thienylgroup; pyridyl group; pyrimidyl group; pyridazinyl group; tetrazolylgroup; pyrrolyl group; oxazolyl group; thiazolyl group; isoxazolylgroup; isothiazolyl group; imidazolyl group; pyrazolyl group;oxadiazolyl group; thiadiazolyl group; and triazolyl group; andparticularly preferred are 2-thienyl group and 3-thienyl group.Unsubstituted groups and substituted groups of the aforementioned groupsare both preferred. Among the substituted groups, those substituted withone or more substituents selected from the group consisting of a C₁₋₆alkyl group which may be substituted with a halogen atom, and a halogenatom are preferred.

The cycloalkyl means a monocyclic alkyl, and it preferably contains, forexample, a 3- to 7-membered ring. Examples of the cycloalkyl include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like, and more preferred are cyclopentyl andcyclohexyl.

Preferred examples of the compounds represented by the formula (1) arementioned below.

Compounds wherein R¹ is hydrogen atom, a halogen atom, hydroxyl group,or amino group, and R³ is a group represented by the formula (1-1);

-   -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is        a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is        a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is        a group represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, a C₂₋₃ alkenyl group, or cyano        group, and R³ is a group represented by the formula (1-1-4), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group, or cyano        group, and R³ is a group represented by the formula (1-1-4), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group, or cyano        group, R³ is a group represented by the formula (1-1-4), or        formula (1-1-7), and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group, or cyano        group, R³ is a group represented by the formula (1-1-4), or        formula (1-1-7), and A³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, or amino group, and R³ is        a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, a C₂₋₃ alkenyl group, or cyano group, and R³        is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, or cyano group, and R³        is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-1-4), or formula (1-1-7),        and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-1-4), or formula (1-1-7),        and A³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, and R³        is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, a C₂₋₃ alkenyl group, or cyano group, and R³        is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, or cyano group, and R³        is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-1-4), or formula (1-1-7),        and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-1-4), or formula (1-1-7),        and A³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, and R³ is a group represented by the        formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, R³ is a group represented by the formula        (1-1), X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single        bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A²,        A³, and A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, R³ is a group represented by the formula        (1-1), X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single        bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³,        and A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, and the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, R³ is a group represented by the formula        (1-1), X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single        bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³,        and A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, and R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆        alkyl), or cyano group, and R³ is a group represented by the        formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        a C₂₋₃ alkenyl group, or cyano group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, ethyl        group, vinyl group, or cyano group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, ethyl        group, vinyl group, or cyano group, R³ is a group represented by        the formula (1-1-7), and A³¹ is hydrogen atom (those compounds        wherein R³ is a group represented by the formula (1-1-4) are        also preferred);

compounds wherein R¹ is hydrogen atom, R² is methyl group, ethyl group,vinyl group, or cyano group, R³ is a group represented by the formula(1-1-7), and A³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group(those compounds wherein R³ is a group represented by the formula(1-1-4) are also preferred);

-   -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, R³ is a group represented        by the formula (1-1), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, R³ is a group represented        by the formula (1-1), and R³¹ is a C₁₋₆ alkyl group substituted        with hydroxyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, and R³ is a        group represented by the formula (1-1);    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), and R³¹ is hydrogen atom;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹, are        hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or        groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is a halogen atom, and        R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is a halogen atom, R³        is a group represented by the formula (1-1), and R³¹ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is a halogen atom, R³        is a group represented by the formula (1-1), and R³¹ is a C₁₋₆        alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³is a group represented by the formula (1-1), R³¹        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1),        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, and R³ is a group represented by the formula        (1-1-1), formula (1-1-2), formula (1-1-3), formula (1-1-4),        formula (1-1-5), formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1-1),        formula (1-1-2), formula (1-1-3), formula (1-1-4), formula        (1-1-5), formula (1-1-6), or formula (1-1-7), and A³¹ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1-1),        formula (1-1-2), formula (1-1-3), formula (1-1-4), formula        (1-1-5), formula (1-1-6), or formula (1-1-7), and A³¹ is a C₁₋₆        alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, and R³ is a group represented by the formula        (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1-4),        or formula (1-1-7), and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1-4),        or formula (1-1-7), and A³¹ is a C₁₋₆ alkyl group substituted        with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-1), and R³¹ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-1), and R³¹ is a        C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring preferably consists of carbon        atoms, or when the ring contains a nitrogen atom to which A³        binds, the ring consists of carbon atoms except for the nitrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, and the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, and the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, and        R³ is a group represented by the formula (1-1-1), formula        (1-1-2), formula (1-1-3), formula (1-1-4), formula (1-1-5),        formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, and        R³ is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1-4), or formula (1-1-7),        and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-1-4), or formula (1-1-7),        and R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, and the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, and the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is hydrogen atom,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1), R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, and R³        is a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, and R³        is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1-7), and R³¹ is hydrogen        atom (those compounds wherein R³ is a group represented by the        formula (1-1-4) are also preferred);    -   compounds wherein R¹ is hydrogen atom, R² is cyano group, R³ is        a group represented by the formula (1-1-7), and R³¹ is a C₁₋₆        alkyl group substituted with hydroxyl group (those compounds        wherein R³ is a group represented by the formula (1-1-4) are        also preferred);    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R³ is a group represented by the formula (1-1), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R³ is a group represented by the formula (1-1), R⁴ is        hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7);        and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7),        and R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-1-4), or formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-1-4), or formula (1-1-7), and R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, 2-methoxyethyl group, 3-hydroxypropyl group, or        3-methoxypropyl group, and R³ is a group represented by the        formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-1), X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl-group, and R³ is a group represented by        the formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7),        and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-1-1), formula (1-1-2), formula (1-1-3), formula        (1-1-4), formula (1-1-5), formula (1-1-6), or formula (1-1-7),        and R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, and R³ is a group represented by        the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-1-4), or formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-1-4), or formula (1-1-7), and R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, 2-(methoxycarbonyl)ethyl group, 3-carboxypropyl group, or        3-(methoxycarbonyl)propyl group, and R³ is a group represented        by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, and R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7), and R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-1-4), or formula (1-1-7), and R³¹        is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-1-4), or formula (1-1-7), and R³¹        is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, and R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-1-1), formula (1-1-2), formula        (1-1-3), formula (1-1-4), formula (1-1-5), formula (1-1-6), or        formula (1-1-7), and R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, and R³ is a group        represented by the formula (1-1-4), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-1-4), or formula (1-1-7), and R³¹        is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-1-4), or formula (1-1-7), and R³¹        is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, 2-methoxyethoxy group, 3-hydroxypropoxy group, or        3-methoxypropoxy group, and R³ is a group represented by the        formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, 3-(hydroxypropyl)amino group,        2-(methoxyethyl)amino group, or 3-(methoxypropyl)amino group,        and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 3-aminopropylamino group, 2-(methylamino)ethylamino        group, 3-(methylamino)propylamino group,        2-(dimethylamino)ethylamino group, or        3-(dimethylamino)propylamino group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, and R³ is a group represented by the formula        (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, and        R³ is a group represented by the formula (1-1-1), formula        (1-1-2), formula (1-1-3), formula (1-1-4), formula (1-1-5),        formula (1-1-6), or formula (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-1-1), formula (1-1-2),        formula (1-1-3), formula (1-1-4), formula (1-1-5), formula        (1-1-6), or formula (1-1-7), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, and        R³ is a group represented by the formula (1-1-4), or formula        (1-1-7);    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-1-4), or formula        (1-1-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-1-4), or formula        (1-1-7), and R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, and R³ is a group represented by the formula        (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group,        ethoxy group, propoxy group, or isopropoxy group, and R³ is a        group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, 3-(methanesulfonyl)propyl group,        2-(ethanesulfonyl)ethyl group, or 3-(ethanesulfonyl)propyl        group, and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-1), X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        ethylthio group, methylsulfinyl group, ethylsulfinyl group,        methanesulfonyl group, or ethanesulfonyl group, and R³ is a        group represented by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, 3-(methanesulfonyl)propoxy        group, 2-(ethanesulfonyl)ethoxy group, or        3-(methanesulfonyl)propoxy group, and R³ is a group represented        by the formula (1-1);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-1), X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is a halogen atom, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is chlorine atom, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, and        R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydroxyl group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, and        R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is amino group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, and R³        is a group represented by the formula (1-1);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is a halogen atom, and        R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-1), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is methyl group, R³ is a        group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is methyl group, R³ is a        group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is a C₁₋₆ alkoxy group, and R³ is a group        represented by the formula (1-1);    -   compounds wherein R¹ is a C₁₋₆ alkoxy group, R² is hydrogen        atom, and R³ is a group represented by the formula (1-1);    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-1), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydrogen atom, a halogen atom, hydroxyl        group, or amino group, and R³ is a group represented by the        formula (1-2);    -   compounds wherein R¹ is hydrogen atom, a halogen atom, hydroxyl        group, or amino group, R³ is a group represented by the formula        (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, and R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C₅)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, and the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2-1), formula (1-2-2),        formula (1-2-3), formula (1-2-4), formula (1-2-5), formula        (1-2-6), or formula (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a        group represented by the formula (1-2-4), or formula (1-2-7),        and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃        alkenyl group, or —S(O)_(p)(C₁₋₆ alkyl), R³ is a group        represented by the formula (1-2-4), or formula (1-2-7), and R⁴        is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group,        hydroxyethyl, or methylthio group, R³ is a group represented by        the formula (1-2-4), or formula (1-2-7), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group, or cyano        group, R³ is a group represented by the formula (1-2-4), or        formula (1-2-7), R⁴ is hydrogen atom, and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, ethyl group, vinyl group,        hydroxyethyl, or methylthio group, R³ is a group represented by        the formula (1-2-4), or formula (1-2-7), R⁴ is hydrogen atom,        and A³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, or amino group, and R³ is        a group represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, or amino group, R³ is a        group represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2-1), formula (1-2-2), formula (1-2-3),        formula (1-2-4), formula (1-2-5), formula (1-2-6), or formula        (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2-4), or formula (1-2-7), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is a        C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        or —S(O)_(p)(C₁₋₆ alkyl), R³ is a group represented by the        formula (1-2-4), or formula (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, hydroxyethyl, or        methylthio group, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-2-4), or formula (1-2-7), R⁴        is hydrogen atom, and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or amino group, R² is        methyl group, ethyl group, vinyl group, hydroxyethyl, or        methylthio group, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), R⁴ is hydrogen atom, and A³¹ is a        C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, and R³        is a group represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R³ is        a group represented-by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2-1), formula (1-2-2), formula (1-2-3),        formula (1-2-4), formula (1-2-5), formula (1-2-6), or formula        (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        —S(O)_(p)(C₁₋₆ alkyl), or cyano group, R³ is a group represented        by the formula (1-2-4), or formula (1-2-7), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group,        or —S(O)_(p)(C₁₋₆ alkyl), R³ is a group represented by the        formula (1-2-4), or formula (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, hydroxyethyl, or        methylthio group, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, or cyano group, R³ is a        group represented by the formula (1-2-4), or formula (1-2-7), R⁴        is hydrogen atom, and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, R² is        methyl group, ethyl group, vinyl group, hydroxyethyl, or        methylthio group, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), R⁴ is hydrogen atom, and A³¹ is a        C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, R³ is a group represented        by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, R³ is a group represented        by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, and R³¹ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, R³ is a group represented        by the formula (1-2), R⁴ is hydrogen atom, and R³¹ is a C₁₋₆        alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, and R³ is a        group represented by the formula (1-2);    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, and R³¹        is hydrogen atom;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, and R³¹        is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, and A¹, A², A³, and A⁵, which may        be identical or different, represent hydrogen atom, or a C₁₋₆        alkyl group, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, and A¹, A², A³, and A⁵, which may        be identical or different, represent hydrogen atom, or a C₁₋₆        alkyl group, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a halogen atom, and R³ is a group represented by        the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a halogen atom, R³ is a group represented by the        formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is a halogen atom, and        R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, R² is a halogen atom, R³        is a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹, which may be identical or different,        represent hydrogen atom, or a C₁₋₆ alkyl group, and A¹, A², A³,        and A⁵, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹, which may be identical or different,        represent hydrogen atom, or a C₁₋₆ alkyl group, and A¹, A², A³,        and A⁵, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³,        and A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or        a single bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms,        A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each of one        or more combinations selected from the group consisting of        combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group, X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a        single bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹,        A², A³, and A⁵ are hydrogen atoms, or groups in each of one or        more combinations selected from the group consisting of        combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or        a single bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms,        A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each of one        or more combinations selected from the group consisting of        combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group, X is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a        single bond, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹,        A², A³, and A⁵ are hydrogen atoms, or groups in each of one or        more combinations selected from the group consisting of        combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, R³¹ is a C₁₋₆ alkyl group substituted with        hydroxyl group, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is hydrogen atom, and R³ is a group represented        by the formula (1-2-1), formula (1-2-2), formula (1-2-3),        formula (1-2-4), formula (1-2-5), formula (1-2-6), or formula        (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is-hydrogen atom, R³ is a group represented by        the formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7),        and A³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is hydrogen atom, R³ is a group represented by        the formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7),        and A³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is hydrogen atom, and R³ is a group represented        by the formula (1-2-4), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is hydrogen atom, R³ is a group represented by        the formula (1-2-4), or formula (1-2-7), and A³¹ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is fluorine atom, or        bromine atom, R⁴ is hydrogen atom, R³ is a group represented by        the formula (1-2-4), or formula (1-2-7), and A³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹, which may be identical or different,        represent hydrogen atom, or a C₁₋₆ alkyl group, and A¹, A², A³,        and A⁵, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹, which may be identical or different,        represent hydrogen atom, or a C₁₋₆ alkyl group, and A¹, A², A³,        and A⁵, which may be identical or different, represent hydrogen        atom, or a C₁₋₆ alkyl group, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, and the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵) 51)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring, the ring consists of        carbon atoms, or when the ring contains a nitrogen atom to which        A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵        are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵ bind to each        other to form a 5- or 6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, and the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—; or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, and A¹, A², A³, and A⁵ are hydrogen atoms, or groups in        each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, and A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, and the ring consists of carbon atoms, or when        the ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A², A³, and A⁵ are hydrogen atoms, or groups in each of        one or more combinations selected from the group consisting of        combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, and the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, and the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom,        R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, and R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, R³ is a group represented by the formula (1-2-1),        formula (1-2-2), formula (1-2-3), formula (1-2-4), formula        (1-2-5), formula (1-2-6), or formula (1-2-7), hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, R³ is a group represented by the formula (1-2-1),        formula (1-2-2), formula (1-2-3), formula (1-2-4), formula        (1-2-5), formula (1-2-6), or formula (1-2-7), alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, and R³ is a group represented by the formula        (1-2-4), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, R³ is a group represented by the formula (1-2-4),        or formula (1-2-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, R³ is a group represented by the formula (1-2-7),        and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methyl group, R⁴ is        hydrogen atom, R³ is a group represented by the formula (1-2-4),        or formula (1-2-7), and R³¹ is a C₁₋₆ alkyl group substituted        with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R³ is a group represented by the formula (1-2), R⁴ is        hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7),        and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7),        and R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-2-4), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-2-4), or formula (1-2-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is hydroxymethyl        group, R⁴ is hydrogen atom, R³ is a group represented by the        formula (1-2-4), or formula (1-2-7), and R³¹ is a C₁₋₆ alkyl        group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, 2-methoxyethyl group, 3-hydroxypropyl group, or        3-methoxypropyl group, R³ is a group represented by the formula        (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A² and A⁵, and A³ and A⁵ bind to each other        to form a 5- or 6-membered ring, the ring consists of carbon        atoms, or when the ring contains a nitrogen atom to which A³        binds, the ring consists of carbon atoms except for the nitrogen        atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, 2-(methoxycarbonyl)ethyl group, 3-carboxypropyl group, or        3-(methoxycarbonyl)propyl group, R³ is a group represented by        the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A² and A⁵, and A³ and A⁵        bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, 2-methoxyethoxy group, 3-hydroxypropoxy group, or        3-methoxypropoxy group, R³ is a group represented by the formula        (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A² and A⁵, and A³ and A⁵ bind to each other        to form a 5- or 6-membered ring, the ring consists of carbon        atoms, or when the ring contains a nitrogen atom to which A³        binds, the ring consists of carbon atoms except for the nitrogen        atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, 3-(hydroxypropyl)amino group,        2-(methoxyethyl)amino group, or 3-(methoxypropyl)amino group, R³        is a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 3-aminopropylamino group, 2-(methylamino)ethylamino        group, 3-(methylamino)propylamino group,        2-(dimethylamino)ethylamino group, or        3-(dimethylamino)propylamino group, R³ is a group represented by        the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-2), R⁴ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A² and A⁵, and A³ and A⁵ bind to each other        to form a 5- or 6-membered ring, the ring consists of carbon        atoms, or when the ring contains a nitrogen atom to which A³        binds, the ring consists of carbon atoms except for the nitrogen        atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, R³¹ is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A² and A⁵, and A³ and A⁵ bind to each other        to form a 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, R³¹ is a C₁₋₆ alkyl group substituted with hydroxyl group,        X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹,        A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, and R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7), and R³¹ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7), and R³¹ is        a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, and R³ is a group represented by the formula        (1-2-4), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, R⁴        is hydrogen atom, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group,        ethoxy group, propoxy group, or isopropoxy group, R³ is a group        represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, 3-(methanesulfonyl)propyl group,        2-(ethanesulfonyl)ethyl group, or 3-(ethanesulfonyl)propyl        group, R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-2), R⁴ is        hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        ethylthio group, methylsulfinyl group, ethylsulfinyl group,        methanesulfonyl group, or ethanesulfonyl group, R³ is a group        represented by the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A² and A⁵, and A³ and A⁵        bind to each other to form a 6-membered ring, the ring consists        of carbon atoms, or when the ring contains a nitrogen atom to        which A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, R³¹ is        hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-2), R⁴ is hydrogen atom, R³¹ is a        C₁₋₆ alkyl group substituted with hydroxyl group, X is        —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and        A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms,        or groups in each of one or more combinations selected from the        group consisting of combinations of A² and A⁵, and A³ and A⁵        bind to each other to form a 6-membered ring, the ring consists        of carbon atoms, or when the ring contains a nitrogen atom to        which A³ binds, the ring consists of carbon atoms except for the        nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-2-1), formula (1-2-2), formula (1-2-3), formula        (1-2-4), formula (1-2-5), formula (1-2-6), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7), and R³¹ is        hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, R³ is a group represented by the formula        (1-2-1), formula (1-2-2), formula (1-2-3), formula (1-2-4),        formula (1-2-5), formula (1-2-6), or formula (1-2-7), and R³¹ is        a C₁₋₆ alkyl group substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, and R³ is a group represented by the        formula (1-2-4), or formula (1-2-7);    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R³¹ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        R⁴ is hydrogen atom, R³ is a group represented by the formula        (1-2-4), or formula (1-2-7), and R³¹ is a C₁₋₆ alkyl group        substituted with hydroxyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, 3-(methanesulfonyl)propoxy        group, 2-(ethanesulfonyl)ethoxy group, or        3-(methanesulfonyl)propoxy group, R³ is a group represented by        the formula (1-2), and R⁴ is hydrogen atom;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-2), R⁴ is        hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is chlorine atom, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, and        R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydroxyl group, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, and        R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom,.R³        is a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹A⁵¹, A⁶, and A⁶¹ are        hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups        in each of one or more combinations selected from the group        consisting of combinations of A¹ and A³, A² and A³, A² and A⁵,        and A³ and A⁵ bind to each other to form a 5- or 6-membered        ring, the ring consists of carbon atoms, or when the ring        contains a nitrogen atom to which A³ binds, the ring consists of        carbon atoms except for the nitrogen atom, and the ring is a        saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is amino group, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, and R³        is a group represented by the formula (1-2);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—, or        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen        atoms, A¹, A², A³, and A⁵ are hydrogen atoms, or groups in each        of one or more combinations selected from the group consisting        of combinations of A¹ and A³, A² and A³, A² and A⁵, and A³ and        A⁵ bind to each other to form a 5- or 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is a halogen atom, and        R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is amino group, R² is a halogen atom, R³ is        a group represented by the formula (1-2), and R⁴ is hydrogen        atom;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-2), R⁴        is hydrogen atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—,        A¹¹, A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and        A⁵ are hydrogen atoms, or groups in each of one or more        combinations selected from the group consisting of combinations        of A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is amino group, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-2), X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is amino group, R² is methyl group, R³ is a        group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹,        A²¹, A⁵¹, A⁶, and A⁶¹, A¹, A², A³, and A⁵ are hydrogen atoms, or        groups in each of one or more combinations selected from the        group consisting of combinations of A¹ and A³, A² and A³, A² and        A⁵, and A³ and A⁵ bind to each other to form a 6-membered ring,        the ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is amino group, R² is methyl group, R³ is a        group represented by the formula (1-2), R⁴ is hydrogen atom, X        is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A² and A⁵, and A³        and A⁵ bind to each other to form a 6-membered ring, the ring        consists of carbon atoms, or when the ring contains a nitrogen        atom to which A³ binds, the ring consists of carbon atoms except        for the nitrogen atom, and the ring is a saturated ring;    -   compounds wherein R¹ is a C₁₋₆ alkoxy group, and R³ is a group        represented by the formula (1-2);    -   compounds wherein R¹ is a C₁₋₆ alkoxy group, R² is hydrogen        atom, and R³ is a group represented by the formula (1-2);    -   compounds wherein R¹ is a C₁₋₆ alkoxy group, R² is hydrogen        atom, R³ is a group represented by the formula (1-2), and R⁴ is        hydrogen atom;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a 5- or        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A¹ and A³,        A² and A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        5- or 6-membered ring, the ring consists of carbon atoms, or        when the ring contains a nitrogen atom to which A³ binds, the        ring consists of carbon atoms except for the nitrogen atom, and        the ring is a saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), X is —C(A⁵)(A⁵¹)—,        —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond, A¹¹, A²¹, A⁵¹, A⁶,        and A⁶¹ are hydrogen atoms, A¹, A², A³, and A⁵ are hydrogen        atoms, or groups in each of one or more combinations selected        from the group consisting of combinations of A¹ and A³, A² and        A³, A² and A⁵, and A³ and A⁵ bind to each other to form a        6-membered ring, the ring consists of carbon atoms, or when the        ring contains a nitrogen atom to which A³ binds, the ring        consists of carbon atoms except for the nitrogen atom, and the        ring is a saturated ring;    -   compounds wherein R¹ is methoxy group, R² is hydrogen atom, R³        is a group represented by the formula (1-2), R⁴ is hydrogen        atom, X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, A¹¹, A²¹,        A⁵¹, A⁶, and A⁶¹ are hydrogen atoms, A¹, A², A^(3, and A) ⁵ are        hydrogen atoms, or groups in each of one or more combinations        selected from the group consisting of combinations of A² and A⁵,        and A³ and A⁵ bind to each other to form a 6-membered ring, the        ring consists of carbon atoms, or when the ring contains a        nitrogen atom to which A³ binds, the ring consists of carbon        atoms except for the nitrogen atom, and the ring is a saturated        ring;    -   compounds wherein R¹ is hydrogen atom, a halogen atom, hydroxyl        group, or amino group, and R³ is a group represented by the        formula (1-3);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, or amino group, and R³ is        a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, or hydroxyl group, and R³        is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is hydrogen atom, a        halogen atom, or a C₁₋₆ alkyl group, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ and R² are hydrogen atoms, and R³ is a        group represented by the formula (1-3);    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), and Y is a C₂₋₆ alkylene        group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), and Y is a C₂₋₄ alkylene        group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, an (aryl)propyl group, a 2-(heteroaryl)ethyl group, a        (heteroaryl)propyl group, a 2-(arylthio)ethyl group, an        (arylthio)propyl group, a 2-(heteroarylthio)ethyl group, a        (heteroarylthio)propyl group, a 2-(arylsulfinyl)ethyl group, an        (arylsulfinyl)propyl, a 2-(heteroarylsulfinyl)ethyl group, a        (heteroarylsulfinyl)propyl group, a 2-(arylsulfonyl)ethyl group,        an (arylsulfonyl)propyl group, a 2-(heteroarylsulfonyl)ethyl        group, or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, an (aryl)propyl group, a        2-(heteroaryl)ethyl group, a (heteroaryl)propyl group, a        2-(arylthio)ethyl group, an (arylthio)propyl group, a        2-(heteroarylthio)ethyl group, a (heteroarylthio)propyl group, a        2-(arylsulfinyl)ethyl group, an (arylsulfinyl)propyl, a        2-(heteroarylsulfinyl)ethyl group, a (heteroarylsulfinyl)propyl        group, a 2-(arylsulfonyl)ethyl group, an (arylsulfonyl)propyl        group, a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, an (aryl)propyl group, a 2-(arylthio)ethyl group, an        (arylthio)propyl group, a 2-(arylsulfinyl)ethyl group, an        (arylsulfinyl)propyl, a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, an (aryl)propyl group, a        2-(arylthio)ethyl group, an (arylthio)propyl group, a        2-(arylsulfinyl)ethyl group, an (arylsulfinyl)propyl, a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, an (aryl)propyl group, a 2-(arylthio)ethyl group, a        2-(arylsulfinyl)ethyl group, or a 2-(arylsulfonyl)ethyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, an (aryl)propyl group, a        2-(arylthio)ethyl group, a 2-(arylsulfinyl)ethyl group, or a        2-(arylsulfonyl)ethyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, or an (aryl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroaryl)ethyl group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(arylthio)ethyl        group, or an (arylthio)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is hydrogen atom, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ and R² are hydrogen atoms, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, and R³ is a group represented        by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a C₁₋₆ alkyl group, R³ is a group represented by        the formula (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is methyl group, or ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a halogen atom, and R³ is a group represented by        the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is a halogen atom, R³ is a group represented by the        formula (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, hydroxyl group, or amino        group, R² is fluorine atom, or bromine atom, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, 2-methoxyethyl group, 3-hydroxypropyl group, or        3-methoxypropyl group, and R³ is a group represented by the        formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, 2-methoxyethyl group, 3-hydroxypropyl group, or        3-methoxypropyl group, R³ is a group represented by the formula        (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), and Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroaryl)ethyl group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a 2-(arylthio)ethyl        group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethyl        group, or 2-methoxyethyl group, R³ is a group represented by the        formula (1-3), Y is ethylene group, or 1,3-propylene group, A⁴        is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, 2-(methoxycarbonyl)ethyl group, 3-carboxypropyl group, or        3-(methoxycarbonyl)propyl group, R³ is a group represented by        the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, 2-(methoxycarbonyl)ethyl group, 3-carboxypropyl group, or        3-(methoxycarbonyl)propyl group, R³ is a group represented by        the formula (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-carboxyethyl        group, or 2-(methoxycarbonyl)ethyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), and Y is a C₂₋₆ alkylene        group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is amino group,        methylamino group, or dimethylamino group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, 2-methoxyethoxy group, 3-hydroxypropoxy group, or        3-methoxypropoxy group, and R³ is a group represented by the        formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, 2-methoxyethoxy group, 3-hydroxypropoxy group, or        3-methoxypropoxy group, R³ is a group represented by the formula        (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, 2-methoxyethoxy group, 3-hydroxypropoxy group, or        3-methoxypropoxy group, R³ is a group represented by the formula        (1-3), and Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroaryl)ethyl group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-hydroxyethoxy        group, or 2-methoxyethoxy group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, 2-(methoxyethyl)amino group,        3-(hydroxypropyl)amino group, or 3-(methoxypropyl)amino group,        and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, 2-(methoxyethyl)amino group,        3-(hydroxypropyl)amino group, or 3-(methoxypropyl)amino group,        R³ is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, 2-(methoxyethyl)amino group,        3-(hydroxypropyl)amino group, or 3-(methoxypropyl)amino group,        R³ is a group represented by the formula (1-3), and Y is        ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(hydroxyethyl)amino group, or 2-(methoxyethyl)amino group, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 3-aminopropylamino group, 2-(methylamino)ethylamino        group, 3-(methylamino)propylamino group,        2-(dimethylamino)ethylamino group, or        3-(dimethylamino)propylamino group, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 3-aminopropylamino group, 2-(methylamino)ethylamino        group, 3-(methylamino)propylamino group,        2-(dimethylamino)ethylamino group, or        3-(dimethylamino)propylamino group, R³ is a group represented by        the formula (1-3), and Y is a C₂₋₆ alkylene group;        3-aminopropylamino group, 2-(methylamino)ethylamino group,        3-(methylamino)propylamino group, 2-(dimethylamino)ethylamino        group, or 3-(dimethylamino)propylamino group, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl        group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroaryl)ethyl group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylthio)ethyl group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is 2-aminoethylamino        group, 2-(methylamino)ethylamino group, or        2-(dimethylamino)ethylamino group, R³ is a group represented by        the formula (1-3), Y is ethylene group, or 1,3-propylene group,        A⁴ is hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkenyl        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkenyl        group, R³ is a group represented by the formula (1-3), and Y is        a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkenyl        group, R³ is a group represented by the formula (1-3), and Y is        ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl group,        or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(heteroaryl)ethyl        group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(arylthio)ethyl        group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethenyl group, or        2-propenyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkynyl        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkynyl        group, R³ is a group represented by the formula (1-3), and Y is        a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₂₋₃ alkynyl        group, R³ is a group represented by the formula (1-3), and Y is        ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(aryl)ethyl group,        or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(heteroaryl)ethyl        group, or a (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a 2-(arylthio)ethyl        group, or an (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylthio)ethyl group, or a (heteroarylthio)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is ethynyl group, or        2-propynyl group, R³ is a group represented by the formula        (1-3), Y is ethylene group, or 1,3-propylene group, A⁴ is        hydrogen atom, or methyl group, and R⁵ is a        2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkoxyl        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkoxyl        group, R³ is a group represented by the formula (1-3), and Y is        a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is a C₁₋₆ alkoxyl        group, R³ is a group represented by the formula (1-3), and Y is        ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methoxy group, or        ethoxy group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, 3-(methanesulfonyl)propyl group,        2-(ethanesulfonyl)ethyl group, or 3-(ethanesulfonyl)propyl        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, 3-(methanesulfonyl)propyl group,        2-(ethanesulfonyl)ethyl group, or 3-(ethanesulfonyl)propyl        group, R³ is a group represented by the formula (1-3), and Y is        a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, 3-(methanesulfonyl)propyl group,        2-(ethanesulfonyl)ethyl group, or 3-(ethanesulfonyl)propyl        group, R³ is a group represented by the formula (1-3), and Y is        ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or        a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethyl group, or 2-(ethanesulfonyl)ethyl        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or        a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        ethylthio group, methylsulfinyl group, ethylsulfinyl group,        methanesulfonyl group, or ethanesulfonyl group, and R³ is a        group represented by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        ethylthio group, methylsulfinyl group, ethylsulfinyl group,        methanesulfonyl group, or ethanesulfonyl group, R³ is a group        represented by the formula (1-3), and Y is a C₂-6 alkylene        group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        ethylthio group, methylsulfinyl group, ethylsulfinyl group,        methanesulfonyl group, or ethanesulfonyl group, R³ is a group        represented by the formula (1-3), and Y is ethylene group, or        1,3-propylene group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylthio)ethyl group, or an (a rylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfinyl)ethyl group, or an (arylsulfinyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(arylsulfonyl)ethyl group, or an (arylsulfonyl)propyl        group;    -   compounds wherein R¹ is hydrogen atom, R² is methylthio group,        methylsulfinyl group, or methanesulfonyl group, R³ is a group        represented by the formula (1-3), Y is ethylene group, or        1,3-propylene group, A⁴ is hydrogen atom, or methyl group, and        R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, 3-(methanesulfonyl)propoxy        group, 2-(ethanesulfonyl)ethoxy group, or        3-(methanesulfonyl)propoxy group, and R³ is a group represented        by the formula (1-3);    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, 3-(methanesulfonyl)propoxy        group, 2-(ethanesulfonyl)ethoxy group, or        3-(methanesulfonyl)propoxy group, R³ is a group represented by        the formula (1-3), and Y is a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, 3-(methanesulfonyl)propoxy        group, 2-(ethanesulfonyl)ethoxy group, or        3-(methanesulfonyl)propoxy group, R³ is a group represented by        the formula (1-3), and Y is ethylene group, or 1,3-propylene        group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or        a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydrogen atom, R² is        2-(methanesulfonyl)ethoxy group, or 2-(ethanesulfonyl)ethoxy        group, R³ is a group represented by the formula (1-3), Y is        ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom, or        methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or        a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, and        R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), and Y is ethylene        group, or 1,3-propylene group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl        group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is chlorine atom, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), and        Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is a halogen atom, and        R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is chlorine atom, R² is a halogen atom, R³        is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3),        and Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is chlorine atom, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, and        R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), and Y is ethylene        group, or 1,3-propylene group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl        group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is hydrogen atom, R³        is a group represented by the formula (1-3), Y is ethylene        group, or 1,3-propylene group, A⁴ is hydrogen atom, or methyl        group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is a C₁₋₆ alkyl        group, and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydroxyl group, R² is a C₁₋₆ alkyl        group, R³ is a group represented by the formula (1-3), and Y is        a C₂₋₆ alkylene group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), and        Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1;3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is a halogen atom,        and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is hydroxyl group, R² is a halogen atom, R³        is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3),        and Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene. group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is hydroxyl group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is amino group, and R³ is a group        represented by the formula (1-3);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, and R³        is a group represented by the formula (1-3);    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), and Y is ethylene        group, or 1,3-propylene group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(aryl)ethyl group, or an (aryl)propyl group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(heteroaryl)ethyl group, or a (heteroaryl)propyl        group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(arylthio)ethyl group, or an (arylthio)propyl        group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(heteroarylsulfinyl)ethyl group, or a        (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is amino group, R² is hydrogen atom, R³ is        a group represented by the formula (1-3), Y is ethylene group,        or 1,3-propylene group, A⁴ is hydrogen atom, or methyl group,        and R⁵ is a 2-(heteroarylsulfonyl)ethyl group, or a        (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is amino group, R² is a C₁₋₆ alkyl group,        and R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is amino group, R² is a C₁₋₆ alkyl group,        R³ is a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), and        Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group;    -   compounds wherein R¹ is amino group, R² is methyl group, or        ethyl group, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group;    -   compounds wherein R¹ is amino group, R² is a halogen atom, and        R³ is a group represented by the formula (1-3);    -   compounds wherein R¹ is amino group, R² is a halogen atom, R³ is        a group represented by the formula (1-3), and Y is a C₂₋₆        alkylene group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3),        and Y is ethylene group, or 1,3-propylene group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(aryl)ethyl group, or an        (aryl)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroaryl)ethyl group, or a        (heteroaryl)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylthio)ethyl group, or an        (arylthio)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylthio)ethyl group, or a        (heteroarylthio)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfinyl)ethyl group, or an        (arylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfinyl)ethyl group,        or a (heteroarylsulfinyl)propyl group;    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(arylsulfonyl)ethyl group, or an        (arylsulfonyl)propyl group; and    -   compounds wherein R¹ is amino group, R² is fluorine atom, or        bromine atom, R³ is a group represented by the formula (1-3), Y        is ethylene group, or 1,3-propylene group, A⁴ is hydrogen atom,        or methyl group, and R⁵ is a 2-(heteroarylsulfonyl)ethyl group,        or a (heteroarylsulfonyl)propyl group.

Further, specific examples of the compounds of the present inventionrepresented by the formula (1) include, for example, the compoundslisted in Tables 1 to 3 mentioned below. The compounds listed in Table 1are compounds having a structure of the formula (1-11), the compoundslisted in Table 2 are compounds having the structure of the formula(1-21), and the compounds listed in Table 3 are compounds having thestructure of the formula (1-31). However, the scope of the presentinvention is not limited to these compounds. TABLE 1 (1-11)

Q1 Q2 Compound Substituent Substituent No. No. No. 1-1 a-1 b-3 1-2 a-1b-4 1-3 a-1 b-5 1-4 a-1 b-6 1-5 a-1 b-7 1-6 a-1 b-8 1-7 a-1 b-9 1-8 a-1b-10 1-9 a-3 b-1 1-10 a-3 b-2 1-11 a-3 b-3 1-12 a-3 b-4 1-13 a-3 b-51-14 a-3 b-6 1-15 a-3 b-10 1-16 a-4 b-1 1-17 a-4 b-2 1-18 a-4 b-3 1-19a-4 b-4 1-20 a-4 b-5 1-21 a-4 b-6 1-22 a-4 b-10 1-23 a-5 b-1 1-24 a-5b-2 1-25 a-5 b-3 1-26 a-5 b-4 1-27 a-5 b-5 1-28 a-5 b-6 1-29 a-5 b-101-30 a-6 b-1 1-31 a-6 b-2 1-32 a-6 b-3 1-33 a-6 b-4 1-34 a-6 b-5 1-35a-6 b-6 1-36 a-6 b-10 1-37 a-7 b-1 1-38 a-7 b-2 1-39 a-7 b-3 1-40 a-7b-4 1-41 a-7 b-5 1-42 a-7 b-6 1-43 a-8 b-1 1-44 a-8 b-2 1-45 a-8 b-31-46 a-8 b-4 1-47 a-8 b-5 1-48 a-8 b-6 1-49 a-9 b-1 1-50 a-9 b-2 1-51a-9 b-3 1-52 a-9 b-4 1-53 a-9 b-5 1-54 a-9 b-6 1-55 a-3 b-7 1-56 a-3 b-81-57 a-3 b-9 1-58 a-10 b-1 1-59 a-10 b-2 1-60 a-10 b-3 1-61 a-10 b-41-62 a-10 b-5 1-63 a-10 b-6 1-64 a-10 b-7 1-65 a-10 b-8 1-66 a-10 b-91-67 a-10 b-10 1-68 a-10 b-11

Among the compounds listed in Table 1, preferred are the compounds ofthe exemplary compound numbers of 1-1, 1-2, 1-3, 1-4, 1-8, 1-9, 1-10,1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22,1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66,1-67, and 1-68.

More preferred compounds are the compounds of the exemplary compoundnumbers of 1-2, i.e., 4-[(5-isoquinolyl)oxy]piperidine; 1-9, i.e.,3-[(1-amino-5-isoquinolyl)oxy]propylamine; and 1-11, i.e.,3-[(1-amino-5-isoquinolyl)oxy]methylpiperidine.

Still more preferred compounds are the compounds of the exemplarycompound numbers of 1-21, i.e.,trans-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine; and 1-63, i.e.,trans-4-[(4-bromo-5-isoquinolyl)oxy]cyclohexylamine.

Further, preferred compounds also includetrans-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine, 4-[(4-cyano-5-isoquinolyl)oxy]piperidine,trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane,1-(2-hydroxyethyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine, and1-(3-hydroxypropyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine. TABLE 2(1-21)

Q1 Q2 Q3 Q1 Q2 Q3 Compound Substituent Substituent Substituent CompoundSubstituent Substituent Substituent No. No. No. No. No. No. No. No. 2-1a-1 b-1 c-1 2-56 a-2 b-1 c-1 2-2 a-1 b-2 c-1 2-57 a-2 b-2 c-1 2-3 a-1b-3 c-1 2-58 a-2 b-3 c-1 2-4 a-1 b-4 c-1 2-59 a-2 b-4 c-1 2-5 a-1 b-5c-1 2-60 a-2 b-5 c-1 2-6 a-1 b-6 c-1 2-61 a-2 b-6 c-1 2-7 a-1 b-7 c-12-62 a-2 b-7 c-1 2-8 a-1 b-8 c-1 2-63 a-2 b-a c-1 2-9 a-1 b-9 c-1 2-64a-2 b-9 c-1 2-10 a-1 b-10 c-1 2-65 a-2 b-10 c-1 2-11 a-1 b-11 c-1 2-66a-2 b-11 c-1 2-12 a-3 b-1 c-1 2-67 a-4 b-1 c-1 2-13 a-3 b-2 c-1 2-68 a-4b-2 c-1 2-14 a-3 b-3 c-1 2-69 a-4 b-3 c-1 2-15 a-3 b-4 c-1 2-70 a-4 b-4c-1 2-16 a-3 b-5 c-1 2-71 a-4 b-5 c-1 2-17 a-3 b-6 c-1 2-72 a-4 b-6 c-12-18 a-3 b-7 c-1 2-73 a-4 b-7 c-1 2-19 a-3 b-8 c-1 2-74 a-4 b-8 c-1 2-20a-3 b-9 c-1 2-75 a-4 b-9 c-1 2-21 a-3 b-10 c-1 2-76 a-4 b-10 c-1 2-22a-3 b-11 c-1 2-77 a-4 b-11 c-1 2-23 a-5 b-1 c-1 2-78 a-6 b-1 c-1 2-24a-5 b-2 c-1 2-79 a-6 b-2 c-1 2-25 a-5 b-3 c-1 2-80 a-6 b-3 c-1 2-26 a-5b-4 c-1 2-81 a-6 b-4 c-1 2-27 a-5 b-5 c-1 2-82 a-6 b-5 c-1 2-28 a-5 b-6c-1 2-83 a-6 b-6 c-1 2-29 a-5 b-7 c-1 2-84 a-6 b-7 c-1 2-30 a-5 b-8 c-12-85 a-6 b-8 c-1 2-31 a-5 b-9 c-1 2-86 a-6 b-9 c-1 2-32 a-5 b-10 c-12-87 a-6 b-10 c-1 2-33 a-5 b-11 c-1 2-88 a-6 b-11 c-1 2-34 a-7 b-1 c-12-89 a-8 b-1 c-1 2-35 a-7 b-2 c-1 2-90 a-8 b-2 c-1 2-36 a-7 b-3 c-1 2-91a-8 b-3 c-1 2-37 a-7 b-4 c-1 2-92 a-8 b-4 c-1 2-38 a-7 b-5 c-1 2-93 a-8b-5 c-1 2-39 a-7 b-6 c-1 2-94 a-8 b-6 c-1 2-40 a-7 b-7 c-1 2-95 a-8 b-7c-1 2-41 a-7 b-8 c-1 2-96 a-8 b-8 c-1 2-42 a-7 b-9 c-1 2-97 a-8 b-9 c-12-43 a-7 b-10 c-1 2-98 a-8 b-10 c-1 2-44 a-7 b-11 c-1 2-99 a-8 b-11 c-12-45 a-9 b-1 c-1 2-100 a-10 b-1 c-1 2-46 a-9 b-2 c-1 2-101 a-10 b-2 c-12-47 a-9 b-3 c-1 2-102 a-10 b-3 c-1 2-48 a-9 b-4 c-1 2-103 a-10 b-4 c-12-49 a-9 b-5 c-1 2-104 a-10 b-5 c-1 2-50 a-9 b-6 c-1 2-105 a-10 b-6 c-12-51 a-9 b-7 c-1 2-106 a-1O b-7 c-1 2-52 a-9 b-8 c-1 2-107 a-10 b-8 c-12-53 a-9 b-9 c-1 2-108 a-10 b-9 c-1 2-54 a-9 b-10 c-1 2-109 a-10 b-10c-1 2-55 a-9 b-11 c-1 2-110 a-10 b-11 c-1 2-111 a-1 b-1 c-2 2-144 a-2b-1 c-2 2-112 a-1 b-2 c-2 2-145 a-2 b-2 c-2 2-113 a-1 b-3 c-2 2-146 a-2b-3 c-2 2-114 a-1 b-4 c-2 2-147 a-2 b-4 c-2 2-115 a-1 b-5 c-2 2-148 a-2b-5 c-2 2-116 a-1 b-6 c-2 2-149 a-2 b-6 c-2 2-117 a-1 b-7 c-2 2-150 a-2b-7 c-2 2-118 a-1 b-8 c-2 2-151 a-2 b-8 c-2 2-119 a-1 b-9 c-2 2-152 a-2b-9 c-2 2-120 a-1 b-b c-2 2-153 a-2 b-b c-2 2-121 a-1 b-11 c-2 2-154 a-2b-11 c-2 2-122 a-3 b-1 c-2 2-155 a-4 b-1 c-2 2-123 a-3 b-2 c-2 2-156 a-4b-2 c-2 2-124 a-3 b-3 c-2 2-157 a-4 b-3 c-2 2-125 a-3 b-4 c-2 2-158 a-4b-4 c-2 2-126 a-3 b-5 c-2 2-159 a-4 b-5 c-2 2-127 a-3 b-6 c-2 2-160 a-4b-6 c-2 2-128 a-3 b-7 c-2 2-161 a-4 b-7 c-2 2-129 a-3 b-8 c-2 2-162 a-4b-8 c-2 2-130 a-3 b-9 c-2 2-163 a-4 b-9 c-2 2-131 a-3 b-b c-2 2-164 a-4b-10 c-2 2-132 a-3 b-11 c-2 2-165 a-4 b-11 c-2 2-133 a-5 b-1 c-2 2-166a-1 b-4 c-3 2-134 a-5 b-2 c-2 2-167 a-1 b-5 c-3 2-135 a-5 b-3 c-2 2-168a-1 b-6 c-3 2-136 a-5 b-4 c-2 2-169 a-1 b-b c-3 2-137 a-5 b-5 c-2 2-170a-2 b-4 c-3 2-138 a-5 b-6 c-2 2-171 a-2 b-5 c-3 2-139 a-5 b-7 c-2 2-172a-2 b-6 c-3 2-140 a-5 b-8 c-2 2-173 a-2 b-10 c-3 2-141 a-5 b-9 c-2 2-174a-3 b-4 c-3 2-142 a-5 b-b c-2 2-175 a-3 b-5 c-3 2-143 a-5 b-11 c-2 2-176a-3 b-6 c-3 2-178 a-11 b-1 c-1 2-177 a-3 b-10 c-3 2-179 a-11 b-2 c-12-189 a-12 b-1 c-1 2-180 a-11 b-3 c-1 2-190 a-12 b-2 c-1 2-181 a-11 b-4c-1 2-191 a-12 b-3 c-1 2-182 a-11 b-5 c-1 2-192 a-12 b-4 c-1 2-183 a-11b-6 c-1 2-193 a-12 b-5 c-1 2-184 a-11 b-7 c-1 2-194 a-12 b-6 c-1 2-185a-11 b-8 c-1 2-195 a-12 b-7 c-1 2-186 a-11 b-9 c-1 2-196 a-12 b-8 c-12-187 a-11 b-b c-1 2-197 a-12 b-9 c-1 2-188 a-11 b-11 c-1 2-198 a-12 b-bc-1 2-200 a-13 b-1 c-1 2-199 a-12 b-11 c-1 2-201 a-13 b-2 c-1 2-206 a-13b-7 c-1 2-202 a-13 b-3 c-1 2-207 a-13 b-8 c-1 2-203 a-13 b-4 c-1 2-208a-13 b-9 c-1 2-204 a-13 b-5 c-1 2-209 a-13 b-10 c-1 2-205 a-13 b-6 c-12-210 a-13 b-11 c-1

Among the compounds listed in Tables 2 and 3, preferred are compounds ofthe exemplary compound numbers of 2-2 to 2-22, 2-24 to 2-30, 2-32, 2-33,2-35 to 2-41, 2-43 to 2-47, 2-57 to 2-77, 2-79 to 2-85, 2-87 to 2-91,2-99, 2-101 to 2-110, 2-114, 2-181 to 2-183, 2-189 to 2-199 and 2-203 to2-205.

More preferred compounds are the compounds of the exemplary compoundnumbers of 2-4, i.e., 4-(5-isoquinolyl)aminopiperidine; 2-6, i.e.,trans-N-(5-isoquinolyl)-1,4-cyclohexanediamine; 2-70, i.e.,4-(4-methyl-5-isoquinolyl)aminopiperidine; 2-72, i.e.,trans-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine; 2-103, i.e.,4-(4-fluoro-5-isoquinolyl)aminopiperidine; 2-104, i.e.,cis-N-(4-fluoro-5-isoquinolyl)-1,4-cyclohexanediamine; 2-105, i.e.,trans-N-(4-fluoro-5-isoquinolyl)-1,4-cyclohexanediamine; 2-181, i.e.,4-(4-bromo-5-isoquinolyl)aminopiperidine; 2-182, i.e.,cis-N-(4-bromo-5-isoquinolyl)-1,4-cyclohexanediamine; 2-183, i.e.,trans-N-(4-bromo-5-isoquinolyl)-1,4-cyclohexanediamine; 2-192, i.e.,4-(4-ethyl-5-isoquinolyl)aminopiperidine; 2-193, i.e.,cis-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine; and 2-194, i.e.,trans-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine.

Further,trans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine isalso a preferred compound. TABLE 3 (1-31)

Q1 Q2 Q3 Q1 Q2 Q3 Compound Substituent Substituent Substituent CompoundSubstituent Substituent Substituent No. No. No. No. No. No. No. No. 3-1a-1 d-1 e-1 3-35 a-1 d-2 e-1 3-2 a-1 d-1 e-2 3-36 a-1 d-2 e-2 3-3 a-1d-1 e-3 3-37 a-1 d-2 e-3 3-4 a-1 d-1 e-4 3-38 a-1 d-2 e-4 3-5 a-1 d-1e-5 3-39 a-1 d-2 e-5 3-6 a-1 d-1 e-6 3-40 a-1 d-2 e-6 3-7 a-1 d-1 e-73-41 a-1 d-2 e-7 3-8 a-1 d-1 e-8 3-42 a-1 d-2 e-8 3-9 a-1 d-1 e-9 3-43a-1 d-2 e-9 3-10 a-1 d-1 e-10 3-44 a-1 d-2 e-10 3-11 a-1 d-1 e-11 3-45a-1 d-2 e-11 3-12 a-1 d-1 e-12 3-46 a-1 d-2 e-12 3-13 a-1 d-1 e-13 3-47a-1 d-2 e-13 3-14 a-1 d-1 e-14 3-48 a-1 d-2 e-14 3-15 a-1 d-1 e-15 3-49a-1 d-2 e-15 3-16 a-1 d-1 e-16 3-50 a-1 d-2 e-16 3-17 a-1 d-1 e-17 3-51a-1 d-Z e-17 3-18 a-1 d-1 e-18 3-52 a-1 d-2 e-18 3-19 a-1 d-1 e-19 3-53a-1 d-2 e-19 3-20 a-1 d-1 e-20 3-54 a-1 d-2 e-20 3-21 a-1 d-1 e-21 3-55a-1 d-2 e-21 3-22 a-1 d-1 e-22 3-56 a-1 d-2 e-22 3-23 a-1 d-1 e-23 3-57a-1 d-2 e-23 3-24 a-1 d-1 e-24 3-58 a-1 d-2 e-24 3-25 a-1 d-1 e-25 3-59a-1 d-2 e-25 3-26 a-1 d-1 e-26 3-60 a-1 d-2 e-26 3-27 a-1 d-1 e-27 3-61a-1 d-2 e-27 3-28 a-1 d-1 e-28 3-62 a-1 d-2 e-28 3-29 a-1 d-1 e-29 3-63a-1 d-2 e-29 3-30 a-1 d-1 e-30 3-64 a-1 d-2 e-30 3-31 a-1 d-1 e-31 3-65a-1 d-2 e-31 3-32 a-1 d-1 e-32 3-66 a-1 d-2 e-32 3-33 a-1 d-1 e-33 3-67a-1 d-2 e-33 3-34 a-1 d-1 e-34 3-68 a-1 d-2 e-34 3-69 a-1 d-3 e-1 3-103a-1 d-4 e-1 3-70 a-1 d-3 e-2 3-104 a-1 d-4 e-2 3-71 a-1 d-3 e-3 3-105a-1 d-4 e-3 3-72 a-1 d-3 e-4 3-106 a-1 d-4 e-4 3-73 a-1 d-3 e-5 3-107a-1 d-4 e-5 3-74 a-1 d-3 e-6 3-108 a-1 d-4 e-6 3-75 a-1 d-3 e-7 3-109a-1 d-4 e-7 3-76 a-1 d-3 e-8 3-110 a-1 d-4 e-8 3-77 a-1 d-3 e-9 3-111a-1 d-4 e-9 3-78 a-1 d-3 e-10 3-112 a-1 d-4 e-10 3-79 a-1 d-3 e-11 3-113a-1 d-4 e-11 3-80 a-1 d-3 e-12 3-114 a-1 d-4 e-12 3-81 a-1 d-3 e-133-115 a-1 d-4 e-13 3-82 a-1 d-3 e-14 3-116 a-1 d-4 e-14 3-83 a-1 d-3e-15 3-117 a-1 d-4 e-15 3-84 a-1 d-3 e-16 3-118 a-1 d-4 e-16 3-85 a-1d-3 e-17 3-119 a-1 d-4 e-17 3-86 a-1 d-3 e-18 3-120 a-1 d-4 e-18 3-87a-1 d-3 e-19 3-121 a-1 d-4 e-19 3-88 a-1 d-3 e-20 3-122 a-1 d-4 e-203-89 a-1 d-3 e-21 3-123 a-1 d-4 e-21 3-90 a-1 d-3 e-22 3-124 a-1 d-4e-22 3-91 a-1 d-3 e-23 3-125 a-1 d-4 e-23 3-92 a-1 d-3 e-24 3-126 a-1d-4 e-24 3-93 a-1 d-3 e-25 3-127 a-1 d-4 e-25 3-94 a-1 d-3 e-26 3-128a-1 d-4 e-26 3-95 a-1 d-3 e-27 3-129 a-1 d-4 e-27 3-96 a-1 d-3 e-283-130 a-1 d-4 e-28 3-97 a-1 d-3 e-29 3-131 a-1 d-4 e-29 3-98 a-1 d-3e-30 3-132 a-1 d-4 e-30 3-99 a-1 d-3 e-31 3-133 a-1 d-4 e-31 3-100 a-1d-3 e-32 3-134 a-1 d-4 e-32 3-101 a-1 d-3 e-33 3-135 a-1 d-4 e-33 3-102a-1 d-3 e-34 3-136 a-1 d-4 e-34 3-137 a-1 d-5 e-1 3-171 a-1 d-6 e-13-138 a-1 d-5 e-2 3-172 a-1 d-6 e-2 3-139 a-1 d-5 e-3 3-173 a-1 d-6 e-33-140 a-1 d-5 e-4 3-174 a-1 d-6 e-4 3-141 a-1 d-5 e-5 3-175 a-1 d-6 e-53-142 a-1 d-5 e-6 3-176 a-1 d-6 e-6 3-143 a-1 d-5 e-7 3-177 a-1 d-6 e-73-144 a-1 d-5 e-8 3-178 a-1 d-6 e-8 3-145 a-1 d-5 e-9 3-179 a-1 d-6 e-93-146 a-1 d-5 e-10 3-180 a-1 d-6 e-10 3-147 a-1 d-5 e-11 3-181 a-1 d-6e-11 3-148 a-1 d-5 e-12 3-182 a-1 d-6 e-12 3-149 a-1 d-5 e-13 3-183 a-1d-6 e-13 3-150 a-1 d-5 e-14 3-184 a-1 d-6 e-14 3-151 a-1 d-5 e-15 3-185a-1 d-6 e-15 3-152 a-1 d-5 e-16 3-186 a-1 d-6 e-16 3-153 a-1 d-5 e-173-187 a-1 d-6 e-17 3-154 a-1 d-5 e-18 3-188 a-1 d-6 e-18 3-155 a-1 d-5e-19 3-189 a-1 d-6 e-19 3-156 a-1 d-5 e-20 3-190 a-1 d-6 e-20 3-157 a-1d-5 e-21 3-191 a-1 d-6 e-21 3-158 a-1 d-5 e-22 3-192 a-1 d-6 e-22 3-159a-1 d-5 e-23 3-193 a-1 d-6 e-23 3-160 a-1 d-5 e-24 3-194 a-1 d-6 e-243-161 a-1 d-5 e-25 3-195 a-1 d-6 e-25 3-162 a-1 d-5 e-26 3-196 a-1 d-6e-26 3-163 a-1 d-5 e-27 3-197 a-1 d-6 e-27 3-164 a-1 d-5 e-28 3-198 a-1d-6 e-28 3-165 a-1 d-5 e-29 3-199 a-1 d-6 e-29 3-166 a-1 d-5 e-30 3-200a-1 d-6 e-30 3-167 a-1 d-5 e-31 3-201 a-1 d-6 e-31 3-168 a-1 d-5 e-323-202 a-1 d-6 e-32 3-169 a-1 d-5 e-33 3-203 a-1 d-6 e-33 3-170 a-1 d-5e-34 3-204 a-1 d-6 e-34 3-205 a-1 d-7 e-1 3-239 a-1 d-8 e-1 3-206 a-1d-7 e-2 3-240 a-1 d-8 e-2 3-207 a-1 d-7 e-3 3-24 1 a-1 d-8 e-3 3-208 a-1d-7 e-4 3-242 a-1 d-8 e-4 3-209 a-1 d-7 e-5 3-243 a-1 d-8 e-5 3-210 a-1d-7 e-6 3-244 a-1 d-8 e-6 3-211 a-1 d-7 e-7 3-245 a-1 d-8 e-7 3-212 a-1d-7 e-8 3-246 a-1 d-8 e-8 3-213 a-1 d-7 e-9 3-247 a-1 d-8 e-9 3-214 a-1d-7 e-10 3-248 a-1 d-8 e-10 3-215 a-1 d-7 e-11 3-249 a-1 d-8 e-11 3-216a-1 d-7 e-12 3-250 a-1 d-8 e-12 3-217 a-1 d-7 e-13 3-251 a-1 d-8 e-133-218 a-1 d-7 e-14 3-252 a-1 d-8 e-14 3-219 a-1 d-7 e-15 3-253 a-1 d-8e-15 3-220 a-1 d-7 e-16 3-254 a-1 d-8 e-16 3-221 a-1 d-7 e-17 3-255 a-1d-8 e-17 3-222 a-1 d-7 e-18 3-256 a-1 d-8 e-18 3-223 a-1 d-7 e-19 3-257a-1 d-8 e-19 3-224 a-1 d-7 e-20 3-258 a-1 d-8 e-20 3-225 a-1 d-7 e-213-259 a-1 d-8 e-21 3-226 a-1 d-7 e-22 3-260 a-1 d-8 e-22 3-227 a-1 d-7e-23 3-261 a-1 d-8 e-23 3-228 a-1 d-7 e-24 3-262 a-1 d-8 e-24 3-229 a-1d-7 e-25 3-263 a-1 d-8 e-25 3-230 a-1 d-7 e-26 3-264 a-1 d-8 e-26 3-231a-1 d-7 e-27 3-265 a-1 d-8 e-27 3-232 a-1 d-7 e-28 3-266 a-1 d-8 e-283-233 a-1 d-7 e-29 3-267 a-1 d-8 e-29 3-234 a-1 d-7 e-30 3-268 a-1 d-8e-30 3-235 a-1 d-7 e-31 3-269 a-1 d-8 e-31 3-236 a-1 d-7 e-32 3-270 a-1d-8 e-32 3-237 a-1 d-7 e-33 3-271 a-1 d-8 e-33 3-238 a-1 d-7 e-34 3-272a-1 d-8 e-34 3-273 a-1 d-9 e-1 3-307 a-2 d-1 e-1 3-274 a-1 d-9 e-2 3-308a-2 d-1 e-2 3-275 a-1 d-9 e-3 3-309 a-2 d-1 e-3 3-276 a-1 d-9 e-4 3-310a-2 d-1 e-4 3-277 a-1 d-9 e-5 3-311 a-2 d-1 e-5 3-278 a-1 d-9 e-6 3-312a-2 d-1 e-6 3-279 a-1 d-9 e-7 3-313 a-2 d-1 e-7 3-280 a-1 d-9 e-8 3-314a-2 d-1 e-8 3-281 a-1 d-9 e-9 3-315 a-2 d-1 e-9 3-282 a-1 d-9 e-10 3-316a-2 d-1 e-10 3-283 a-1 d-9 e-11 3-317 a-2 d-1 e-11 3-284 a-1 d-9 e-123-318 a-2 d-1 e-12 3-285 a-1 d-9 e-13 3-319 a-2 d-1 e-13 3-286 a-1 d-9e-14 3-320 a-2 d-1 e-14 3-287 a-1 d-9 e-15 3-321 a-2 d-1 e-15 3-288 a-1d-9 e-16 3-322 a-2 d-1 e-16 3-289 a-1 d-9 e-17 3-323 a-2 d-1 e-17 3-290a-1 d-9 e-18 3-324 a-2 d-1 e-18 3-291 a-1 d-9 e-19 3-325 a-2 d-1 e-193-292 a-1 d-9 e-20 3-326 a-2 d-1 e-20 3-293 a-1 d-9 e-21 3-327 a-2 d-1e-21 3-294 a-1 d-9 e-22 3-328 a-2 d-1 e-22 3-295 a-1 d-9 e-23 3-329 a-2d-1 e-23 3-296 a-1 d-9 e-24 3-330 a-2 d-1 e-24 3-297 a-1 d-9 e-25 3-331a-2 d-1 e-25 3-298 a-1 d-9 e-26 3-332 a-2 d-1 e-26 3-299 a-1 d-9 e-273-333 a-2 d-1 e-27 3-300 a-1 d-9 e-28 3-334 a-2 d-1 e-28 3-301 a-1 d-9e-29 3-335 a-2 d-1 e-29 3-302 a-1 d-9 e-30 3-336 a-2 d-1 e-30 3-303 a-1d-9 e-31 3-337 a-2 d-1 e-31 3-304 a-1 d-9 e-32 3-338 a-2 d-1 e-32 3-305a-1 d-9 e-33 3-339 a-2 d-1 e-33 3-306 a-1 d-9 e-34 3-340 a-2 d-1 e-343-341 a-2 d-2 e-1 3-375 a-2 d-3 e-1 3-342 a-2 d-2 e-2 3-376 a-2 d-3 e-23-343 a-2 d-2 e-3 3-377 a-2 d-3 e-3 3-344 a-2 d-2 e-4 3-378 a-2 d-3 e-43-345 a-2 d-2 e-5 3-379 a-2 d-3 e-5 3-346 a-2 d-2 e-6 3-380 a-2 d-3 e-63-347 a-2 d-2 e-7 3-381 a-2 d-3 e-7 3-348 a-2 d-2 e-8 3-382 a-2 d-3 e-83-349 a-2 d-2 e-9 3-383 a-2 d-3 e-9 3-350 a-2 d-2 e-10 3-384 a-2 d-3e-10 3-351 a-2 d-2 e-11 3-385 a-2 d-3 e-11 3-352 a-2 d-2 e-12 3-386 a-2d-3 e-12 3-353 a-2 d-2 e-13 3-387 a-2 d-3 e-13 3-354 a-2 d-2 e-14 3-388a-2 d-3 e-14 3-355 a-2 d-2 e-15 3-389 a-2 d-3 e-15 3-356 a-2 d-2 e-163-390 a-2 d-3 e-16 3-357 a-2 d-2 e-17 3-391 a-2 d-3 e-17 3-358 a-2 d-2e-18 3-392 a-2 d-3 e-18 3-359 a-2 d-2 e-19 3-393 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d-2 e-31 3-780 a-5 d-1 e-32 3-814 a-5 d-2 e-32 3-781a-5 d-1 e-33 3-815 a-5 d-2 e-33 3-782 a-5 d-1 e-34 3-816 a-5 d-2 e-343-817 a-6 d-1 e-1 3-851 a-6 d-2 e-1 3-818 a-6 d-1 e-2 3-852 a-6 d-2 e-23-819 a-6 d-1 e-3 3-853 a-6 d-2 e-3 3-820 a-6 d-1 e-4 3-854 a-6 d-2 e-43-821 a-6 d-1 e-5 3-855 a-6 d-2 e-5 3-822 a-6 d-1 e-6 3-856 a-6 d-2 e-63-823 a-6 d-1 e-7 3-857 a-6 d-2 e-7 3-824 a-6 d-1 e-8 3-858 a-6 d-2 e-83-825 a-6 d-1 e-9 3-859 a-6 d-2 e-9 3-826 a-6 d-1 e-10 3-860 a-6 d-2e-10 3-827 a-6 d-1 e-11 3-861 a-6 d-2 e-11 3-828 a-6 d-1 e-12 3-862 a-6d-2 e-12 3-829 a-6 d-1 e-13 3-863 a-6 d-2 e-13 3-830 a-6 d-1 e-14 3-864a-6 d-2 e-14 3-831 a-6 d-1 e-15 3-865 a-6 d-2 e-15 3-832 a-6 d-1 e-163-866 a-6 d-2 e-16 3-833 a-6 d-1 e-17 3-867 a-6 d-2 e-11 3-834 a-6 d-1e-18 3-868 a-6 d-2 e-18 3-835 a-6 d-1 e-19 3-869 a-6 d-2 e-19 3-836 a-6d-1 e-20 3-870 a-6 d-2 e-20 3-837 a-6 d-1 e-21 3-871 a-6 d-2 e-21 3-838a-6 d-1 e-22 3-872 a-6 d-2 e-22 3-839 a-6 d-1 e-23 3-873 a-6 d-2 e-233-840 a-6 d-1 e-24 3-874 a-6 d-2 e-24 3-841 a-6 d-1 e-25 3-875 a-6 d-2e-25 3-842 a-6 d-1 e-26 3-876 a-6 d-2 e-26 3-843 a-6 d-1 e-27 3-877 a-6d~2 e-27 3-844 a-6 d-1 e-28 3-878 a-6 d-2 e-28 3-845 a-6 d-1 e-29 3-879a-6 d-2 e-29 3-846 a-6 d-1 e-30 3-880 a-6 d-2 e-30 3-847 a-6 d-1 e-313-881 a-6 d-2 e-31 3-848 a-6 d-1 e-32 3-882 a-6 d-2 e-32 3-849 a-6 d-1e-33 3-883 a-6 d-2 e-33 3-850 a-6 d-1 e-34 3-884 a-6 d-2 e-34 3-885 a-7d-1 e-1 3-919 a-7 d-2 e-1 3-886 a-7 d-1 e-2 3-920 a-7 d-2 e-2 3-887 a-7d-1 e-3 3-921 a-7 d-2 e-3 3-888 a-7 d-1 e-4 3-922 a-7 d-2 e-4 3-889 a-7d-1 e-5 3-923 a-7 d-2 e-5 3-890 a-7 d-1 e-6 3-924 a-7 d-2 e-6 3-891 a-7d-1 e-7 3-925 a-1 d-2 e-7 3-892 a-7 d-1 e-8 3-926 a-7 d-2 e-8 3-893 a-7d-1 e-9 3-927 a-7 d-2 e-9 3-894 a-7 d-1 e-10 3-928 a-7 d-2 e-10 3-895a-7 d-1 e-11 3-929 a-7 d-2 e-11 3-896 a-7 d-1 e-12 3-930 a-1 d-2 e-123-897 a-7 d-1 e-13 3-931 a-1 d-2 e-13 3-898 a-7 d-1 e-14 3-932 a-1 d-2e-14 3-899 a-7 d-1 e-15 3-933 a-1 d-2 e-15 3-900 a-1 d-1 e-16 3-934 a-1d-2 e-16 3-901 a-1 d-1 e-11 3-935 a-1 d-2 e-17 3-902 a-1 d-1 e-18 3-936a-1 d-2 e-18 3-903 a-1 d-1 e-19 3-937 a-1 d-2 e-19 3-904 a-1 d-1 e-203-938 a-1 d-2 e-20 3-905 a-1 d-1 e-21 3-939 a-1 d-2 e-21 3-906 a-1 d-1e-22 3-940 a-1 d-2 e-22 3-907 a-1 d-1 e-23 3-941 a-1 d-2 e-23 3-908 a-1d-1 e-24 3-942 a-1 d-2 e-24 3-909 a-1 d-1 e-25 3-943 a-1 d-2 e-25 3-910a-1 d-1 e-26 3-944 a-1 d-2 e-26 3-911 a-1 d-1 e-27 3-945 a-1 d-2 e-273-912 a-1 d-1 e-28 3-946 a-1 d-2 e-28 3-913 a-1 d-1 e-29 3-947 a-1 d-2e-29 3-914 a-1 d-1 e-30 3-948 a-1 d-2 e-30 3-915 a-1 d-1 e-31 3-949 a-1d-2 e-31 3-916 a-1 d-1 e-32 3-950 a-1 d-2 e-32 3-917 a-1 d-1 e-33 3-951a-1 d-2 e-33 3-918 a-7 d-1 e-34 3-952 a-7 d-2 e-34 3-953 a-8 d-1 e-13-987 a-8 d-2 e-1 3-954 a-8 d-1 e-2 3-988 a-8 d-2 e-2 3-955 a-8 d-1 e-33-989 a-8 d-2 e-3 3-956 a-8 d-1 e-4 3-990 a-8 d-2 e-4 3-957 a-8 d-1 e-53-991 a-8 d-2 e-5 3-95B a-8 d-1 e-6 3-992 a-8 d-2 e-6 3-959 a-8 d-1 e-73-993 a-8 d-2 e-7 3-960 a-8 d-1 e-8 3-994 a-8 d-2 e-8 3-96 1 a-8 d-1 e-93-995 a-8 d-2 e-9 3-962 a-8 d-1 e-10 3-996 a-8 d-2 e-10 3-963 a-8 d-1e-11 3-997 a-8 d-2 e-11 3-964 a-8 d-1 e-12 3-998 a-8 d-2 e-12 3-965 a-8d-1 e-13 3-999 a-8 d-2 e-13 3-966 a-8 d-1 e-14 3-1000 a-8 d-2 e-14 3-967a-8 d-1 e-15 3-1001 a-8 d-2 e-15 3-96B a-8 d-1 e-16 3-1002 a-8 d-2 e-163-969 a-8 d-1 e-17 3-1003 a-8 d-2 e-17 3-970 a-8 d-1 e-18 3-1004 a-8 d-2e-18 3-971 a-8 d-1 e-19 3-1005 a-8 d-2 e-19 3-972 a-8 d-1 e-20 3-1006a-8 d-2 e-20 3-973 a-8 d-1 e-21 3-1007 a-8 d-2 e-21 3-974 a-8 d-1 e-223-1008 a-8 d-2 e-22 3-975 a-8 d-1 e-23 3-1009 a-8 d-2 e-23 3-976 a-8 d-1e-24 3-1010 a-8 d-2 e-24 3-977 a-8 d-1 e-25 3-1011 a-8 d-2 e-25 3-978a-8 d-1 e-26 3-1012 a-8 d-2 e-26 3-979 a-8 d-1 e-27 3-1013 a-8 d-2 e-273-980 a-8 d-1 e-28 3-1014 a-8 d-2 e-28 3-981 a-8 d-1 e-29 3-1015 a-8 d-2e-29 3-982 a-8 d-1 e-30 3-1016 a-8 d-2 e-30 3-983 a-8 d-1 e-31 3-1017a-8 d-2 e-31 3-984 a-8 d-1 e-32 3-1018 a-8 d-2 e-32 3-985 a-8 d-1 e-333-1019 a-8 d-2 e-33 3-986 a-8 d-1 e-34 3-1020 a-8 d-2 e-34 3-1021 a-9d-1 e-1 3-1055 a-9 d-2 e-1 3-1022 a-9 d-1 e-2 3-1056 a-9 d-2 e-2 3-1023a-9 d-1 e-3 3-1057 a-9 d-2 e-3 3-1024 a-9 d-1 e-4 3-1058 a-9 d-2 e-43-1025 a-9 d-1 e-5 3-1059 a-9 d-2 e-5 3-1026 a-9 d-1 e-6 3-1060 a-9 d-2e-6 3-1027 a-9 d-1 e-7 3-1061 a-9 d-2 e-7 3-1028 a-9 d-1 e-8 3-1062 a-9d-2 e-8 3-1029 a-9 d-1 e-9 3-1063 a-9 d-2 e-9 3-1030 a-9 d-1 e-10 3-1064a-9 d-2 e-10 3-1031 a-9 d-1 e-11 3-1065 a-9 d-2 e-11 3-1032 a-9 d-1 e-123-1066 a-9 d-2 e-12 3-1033 a-9 d-1 e-13 3-1067 a-9 d-2 e-13 3-1034 a-9d-1 e-14 3-1068 a-9 d-2 e-14 3-1035 a-9 d-1 e-15 3-1069 a-9 d-2 e-153-1036 a-9 d-1 e-16 3-1070 a-9 d-2 e-16 3-1037 a-9 d-1 e-17 3-1071 a-9d-2 e-17 3-1038 a-9 d-1 e-18 3-1072 a-9 d-2 e-18 3-1039 a-9 d-1 e-193-1073 a-9 d-2 e-19 3-1040 a-9 d-1 e-20 3-1074 a-9 d-2 e-20 3-1041 a-9d-1 e-21 3-1075 a-9 d-2 e-21 3-1042 a-9 d-1 e-22 3-1076 a-9 d-2 e-223-1043 a-9 d-1 e-23 3-1077 a-9 d-2 e-23 3-1044 a-9 d-1 e-24 3-1078 a-9d-2 e-24 3-1045 a-9 d-1 e-25 3-1079 a-9 d-2 e-25 3-1046 a-9 d-1 e-263-1080 a-9 d-2 e-26 3-1047 a-9 d-1 e-27 3-1081 a-9 d-2 e-27 3-1048 a-9d-1 e-28 3-1082 a-9 d-2 e-28 3-1049 a-9 d-1 e-29 3-1083 a-9 d-2 e-293-1050 a-9 d-1 e-30 3-1084 a-9 d-2 e-30 3-1051 a-9 d-1 e-31 3-1085 a-9d-2 e-31 3-1052 a-9 d-1 e-32 3-1086 a-9 d-2 e-32 3-1053 a-9 d-1 e-333-1087 a-9 d-2 e-33 3-1054 a-9 d-1 e-34 3-1088 a-9 d-2 e-34 3-1089 a-10d-1 e-1 3-1123 a-10 d-2 e-1 3-1090 a-10 d-1 e-2 3-1124 a-10 d-2 e-23-1091 a-10 d-1 e-3 3-1125 a-10 d-2 e-3 3-1092 a-10 d-1 e-4 3-1126 a-10d-2 e-4 3-1093 a-10 d-1 e-5 3-1127 a-10 d-2 e-5 3-1094 a-10 d-1 e-63-1128 a-10 d-2 e-6 3-1095 a-10 d-1 e-7 3-1129 a-10 d-2 e-7 3-1096 a-10d-1 e-8 3-1130 a-10 d-2 e-8 3-1097 a-10 d-1 e-9 3-1131 a-10 d-2 e-93-1098 a-10 d-1 e-10 3-1132 a-10 d-2 e-10 3-1099 a-10 d-1 e-11 3-1133a-10 d-2 e-11 3-1100 a-10 d-1 e-12 3-1134 a-10 d-2 e-12 3-1101 a-10 d-1e-13 3-1135 a-10 d-2 e-13 3-1102 a-10 d-1 e-14 3-1136 a-10 d-2 e-143-1103 a-10 d-1 e-15 3-1137 a-10 d-2 e-15 3-1104 a-10 d-1 e-16 3-1138a-10 d-2 e-16 3-1105 a-10 d-1 e-17 3-1139 a-10 d-2 e-17 3-1106 a-10 d-1e-18 3-1140 a-10 d-2 e-18 3-1107 a-10 d-1 e-19 3-1141 a-10 d-2 e-193-1108 a-10 d-1 e-20 3-1142 a-10 d-2 e-20 3-1109 a-10 d-1 e-21 3-1143a-10 d-2 e-21 3-1110 a-10 d-1 e-22 3-1144 a-10 d-2 e-22 3-1111 a-10 d-1e-23 3-1145 a-10 d-2 e-23 3-1112 a-10 d-1 e-24 3-1146 a-10 d-2 e-243-1113 a-10 d-1 e-25 3-1147 a-10 d-2 e-25 3-1114 a-10 d-1 e-26 3-1148a-10 d-2 e-26 3-1115 a-10 d-1 e-27 3-1149 a-10 d-2 e-27 3-1116 a-10 d-1e-28 3-1150 a-10 d-2 e-28 3-1117 a-10 d-1 e-29 3-1151 a-10 d-2 e-293-1118 a-10 d-1 e-30 3-1152 a-10 d-2 e-30 3-1119 a-10 d-1 e-31 3-1153a-10 d-2 e-31 3-1120 a-10 d-1 e-32 3-1154 a-10 d-2 e-32 3-1121 a-10 d-1e-33 3-1155 a-10 d-2 e-33 3-1122 a-10 d-1 e-34 3-1156 a-10 d-2 e-34

Among the compounds listed in Table 3, preferred are the compounds ofthe exemplary compound numbers of 3-1 to 3-12, 3-35 to 3-46, 2-307 to2-318, 3-341 to 3-352, 3-613 to 3-624, 3-647 to 3-658, 3-681 to 3-692,and 3-715 to 3-726.

More preferred compounds are the compounds of the exemplary compoundnumbers of 3-1, i.e.,N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine; 3-12,i.e.,N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;3-35, i.e.,N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;3-37, i.e.,N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;3-46, i.e.,N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;3-47, i.e.,N-[(5-isoquinolyl)sulfonyl]-N-(4-phenylbutyl)-1,3-propylenediamine;3-205, i.e.,4-{N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)}aminopiperidine;3-318, i.e.,N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;3-341, i.e., N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-p ropylenediamine; 3-352, i.e.,N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine; 3-624, i.e., N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;3-647, i.e., N-[(1- amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine; and3-715, i.e.,N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine.

In the formulas (1-11), (1-21), and (1-31), the substituent of Q¹ is anyof the following groups.

In the formulas (1-11) and (1-21), the substituent of Q² is any of thefollowing groups.

In the formula (1-21), the substituent of Q³ is any of the followinggroups.

In the formula (1-31), the substituent of Q⁴ is any of the followinggroups.

In the formula (1-31), the substituent of Q⁵ is any of the followinggroups.

The compounds of the present invention represented by the formula (1)may have one or more asymmetric carbons, and stereoisomers based on suchasymmetric carbons such as optical antipodes and diastereoisomer mayexist. The stereoisomers in pure forms, any mixtures, racemates and thelike of the stereoisomers all fall within the scope of the presentinvention. Further, when the compounds of the present invention have anolefinic double bond or a cyclic structure, two or more kinds ofstereoisomers may exist, and such stereoisomers in pure forms, anymixtures, racemates and the like of such stereoisomers all fall withinthe scope of the present invention. Furthermore, the compounds of thepresent invention represented by the formula (1) may exist as tautomers.Existence of such tautomers is apparent to those skilled in the art, andsuch tautomers all fall within the scope of the present invention.

The compounds of the present invention may also exist as salts. Forms ofthe salts are not particularly limited. Acid addition salts aregenerally formed, or base addition salts may be formed depending on thetypes of substituents. The types of physiologically acceptable salts arewell known to those skilled in the art, and examples include, forexample, those described by Berge et al. in J. Pharm. Sci., 66, 1-19(1977). Examples of the acid addition salts include, for example,mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides,nitrates, sulfates, and hydrogensulfates, phosphates,hydrogenphosphates, organic acid salts such as acetates,trifluoroacetates, gluconates, lactates, salicylates, citrates,tartrates, ascorbates, succinates, maleates, fumarates, formates,benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates andp-toluenesulfonates. Where one or more substituents contain an acidicmoiety, examples of suitable pharmacologically acceptable base additionsalts include, for example, metal salts such as sodium salts, potassiumsalts, magnesium salts, lithium salts, calcium salts, aluminum salts andzinc salts, and salts of organic amines such as ethanolamine.

Methods for preparation of the compounds represented by the formula (1)are not particularly limited. For example, they can be preparedaccording to the methods described below.

That is, the compounds represented by the formula (1) wherein A³¹ ishydrogen atom can be prepared by removing a protective group (PG) of anamino group of a compound represented by the following formula (A):

wherein R¹ and R² have the same meanings as those defined above; and R³¹represent a group represented by the following formula (a-1), (a-2), or(a-3):

wherein A¹, A¹¹, A², A²¹, A³, A⁴, X, Y, R⁴ and R⁵ have the same meaningsas those defined above, and PG represents a protective group for theamino group. The PG group used herein is not particularly limited solong as it can protect the amino group, does not react in reactionsother than the deprotection step in this preparation process, and can beeasily removed. Preferred examples include t-butoxycarbonyl group (Bocgroup) and benzyloxycarbonyl group (Cbz group), and a particularlypreferred example is Boc group.

For example, when PG is Boc group, the Boc group can be removed from acompound of the formula (A) to prepare a compound of the formula (1) byusing known acidic conditions. Examples of the solvent used for thereaction include, for example, water, alcohols, ether solvents such as1,4-dioxane and a mixed solvent thereof. As the acid, a mineral acid canbe used. Specific examples include hydrochloric acid, sulfuric acid,nitric acid, and phosphoric acid, and hydrochloric acid is preferred. Asfor the amount of the acid used, it is preferable to use 1 to 100 molesbased on the compound of the formula (A). The reaction is preferablyperformed in the temperature range of from room temperature to thereflux temperature of the solvent.

Alternatively, the deprotection can be performed by usingtrifluoroacetic acid. Examples of the method include a method of usingtrifluoroacetic acid alone, and a method of using trifluoroacetic acidas a mixed solvent system with water or dichloromethane. The reaction isperformed, for example, in the temperature range of from 0 to 100° C.,preferably from room temperature to 50° C. As for the amount oftrifluoroacetic acid, 1 to 100 moles are preferably used based on thecompound of the formula (A).

Further,. when PG is Cbz group, a method for removing the Cbz group fromthe compound of the formula (A) to prepare a compound (1) can be carriedout by using a condition of known hydrogenation reduction. Examples ofthe method include a method of performing the hydrogenation in analcohol, ethyl acetate, an ether solvent such as 1,4-dioxane, or a mixedsolvent thereof, and examples of the catalyst include, for example,palladium carbon. The reaction can be performed at a temperature of, forexample, from 0 to 80° C., preferably from 10 to 40° C.

By referring to prior art described in, for example, Greene, T. W. andWuts, P. G. M. “Protective Groups in Organic Synthesis”, John Wiley andSons Inc. (3rd edition) and Kocienski, P. J., “Protecting Groups”, GeorgThieme Verlag (1994), it will be apparent to those skilled in the artthat a particular functional group can be protected by an appropriateprotective group, and then deprotected in the synthesis examples shownin this specification.

The compounds represented by the formula (1) wherein A³¹ is a C₁₋₆ alkylgroup substituted with hydroxyl group can be prepared by subjecting acompound of the formula (1) wherein A³¹ is hydrogen atom to asubstitution reaction using a C₁₋₆ alkylating agent substituted withhydroxyl group. Examples of the alkylating agent include alkyl halides,alkyl tosylates, and alkyl mesylates. The reaction is usually performedin the presence of a base. An inorganic base is preferred, and examplesinclude potassium carbonate, sodium hydrogencarbonate, potassiumhydride, and sodium hydride.

The alkylating agent is preferably used in an amount of 1 to 10 moles.The reaction is preferably performed at a temperature of from −10 to 80°C., and the reaction time is preferably from 0.5 to 48 hours.

Examples of the reaction solvent include alcoholic solvents such asmethanol and ethanol, and inert solvents such as dimethylformamide,dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetone, dimethylsulfoxide, and acetonitrile.

Moreover, as for the introduction of the C₁₋₆ alkyl group substitutedwith hydroxyl group, it may be preferable to perform the substitutionreaction with a C₁₋₆ alkylating agent substituted with a protectedhydroxyl group and then deprotect the hydroxyl group. Examples of theprotective group of hydroxyl group include a trialkylsilyl group such astert-butyldimethylsilyl group (TBDMS group), an acyl group such asacetyl group, benzyl group (Bn group), and tetrahydropyranyl (THP)group, and preferred examples include tetrahydropyranyl (THP) group. Forexample, the objective compounds can be prepared by subjecting acompound of the formula (1) wherein A³¹ is hydrogen atom to asubstitution reaction using an alkylating agent substituted withhydroxyl group protected with tetrahydropyranyl (THP) group, and thenperforming deprotection for the THP group under a known acidiccondition. As for the removal of THP, examples of the solvent used forthe reaction include water, alcohols, ether solvents such as 1,4-dioxaneand mixed solvents of these. As the acid, mineral acids can be used, andspecific examples are hydrochloric acid, sulfuric acid, nitric acid, andphosphoric acid. The acid is preferably used in an amount of 1 to 100moles. The reaction is preferably performed in the temperature range offrom room temperature to the reflux temperature of the solvent.

The compounds of the formula (A) wherein R¹ is hydroxyl group, or a C₁₋₆alkoxyl group can be prepared from a compound represented by thefollowing formula (B):

wherein R² and R³¹ have the same meanings as those defined above. Thatis, by hydrolyzing a compound of the formula (B), a compound of theformula (A) wherein R¹ is hydroxyl group can be obtained. The hydrolysisis preferably carried out in a mineral acid. Examples of the mineralacid to be used include hydrochloric acid, sulfuric acid, nitric acidand the like, and particularly preferred examples are hydrochloric acidand sulfuric acid. The acid is preferably used in an amount of 1 to 100moles based on the compound of the formula (B). The reaction is carriedout at a temperature of, for example, from room temperature to 200° C.However, depending on type of the protective group of R³¹ or reactionconditions, the reaction may proceed to a compound of the formula (1)wherein the PG group of R³¹ is removed, not a compound of the formula(A). The reaction time is preferably from 0.1 to 48 hours.

Further, by using a desired C₁₋₆ alcohol instead of water as a solventin the aforementioned reaction using the compound of the formula (B), acompound of the formula (A) wherein R¹ is a corresponding C₁₋₆ alkoxylgroup can be obtained. The C₁₋₆ alcohol to be used is preferably used ina large excess amount. However, depending on type of the protectivegroup of R³¹ or reaction conditions, the reaction may proceed to acompound of the formula (1) wherein the PG group of R³¹ is removed, nota compound of the formula (A).

The compounds of the formula (A) wherein R¹ is amino group can beobtained by aminating a compound of the formula (B). The reaction can beperformed by, for example, using aqueous ammonia at a concentration offrom 2 to 28%, and examples of the method include a method of performingthe reaction in the temperature range of from room temperature to 200°C. The reaction time is preferably from 0.1 to 48 hours.

Alternatively, the compounds of the formula (A) wherein R¹ is aminogroup can be prepared by converting a compound of the formula (B) into acompound of the formula (B) in which the chlorine atom is converted into4-methoxybenzylamino group and then removing the 4-methoxybenzyl moietyby an acidolysis reaction. That is, the conversion into4-methoxybenzylamino group can be first carried out by using4-methoxybenzylamine in an inert solvent in the presence of a palladiumcatalyst, phosphorus compound, and base (according to, for example,Buchwald, S. L., J. Org. Chem., 1158 (2000); Buchwald, S. L., OrganicLetters, 1101 (2000)). Examples of the inert solvent include ether typesolvents such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane,toluene, and N,N-dimethylformamide. Examples of the palladium catalystinclude tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetateand the like. Examples of the phosphorus compound include2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, andtri(tert-butyl)phosphine. Further, examples of the base include sodiumtert-butoxide, cesium carbonate, potassium phosphate and the like.4-Methoxybenzylamine is preferably used in an amount of 1 to 10 moles.

The removal of the 4-methoxybenzyl moiety is preferably performed by adecomposition reaction using an acid. Examples of the solvent used forthe reaction include, for example, water, alcohols, ether type solventssuch as 1,4-dioxane and mixed solvents of these. As the acid, a mineralacid can be used. Specific examples include hydrochloric acid, sulfuricacid, nitric acid, and phosphoric acid, and hydrochloric acid is apreferred example. The acid is preferably used in an amount of from 1 to100 moles. The reaction is preferably performed in the temperature rangeof from room temperature to reflux temperature of the solvent.Alternatively, a method of using trifluoroacetic acid alone, or a methodof using trifluoroacetic acid as a mixed solvent system with water ordichloromethane can be mentioned. The reaction is performed, forexample, in the temperature range of from 0 to 100° C., preferably fromroom temperature to 50° C.

However, depending on type of the protective group of R³¹ or reactionconditions, the reaction may proceed to a compound of the formula (1)wherein the PG group of R³¹ is removed, not a compound of the formula(A).

The compounds of the formula (A) wherein R¹ is chlorine atom can beobtained as compounds of the formula (B), per se, as described later,and further, the compounds of the formula (A) wherein R¹ is a halogenatom other than chlorine atom can be prepared by a halogen exchangereaction of a compound of the formula (B). For example, by usingpotassium fluoride or cesium fluoride as an alkali halide, a compound ofthe formula (A) wherein R¹ is fluorine atom can be synthesized.

The compounds of the formula (A) wherein R¹ is chlorine atom(corresponding to the compounds of the formula (B)) can be prepared froma compound represented by the following formula (C):

wherein R² and R³¹ have the same meanings as those defined above. It ispreferable to chlorinate a compound of the formula (C) with achlorinating reagent to convert it into a compound of the formula (B).As for the solvent, the reaction can be performed, for example, withoutsolvent or in an inert solvent. Examples of the inert solvent includedichloromethane, 1,2-dichloroethane, chloroform, and toluene. Examplesof the chlorinating reagent include phosphorus trichloride, phosphoruspentachloride, and phosphorus oxychloride. The chlorinating reagent ispreferably used in an amount of from 1 to 10 moles based on the compoundof the formula (C). The reaction is preferably performed at atemperature of from room temperature to about 100° C. The reaction timeis preferably from 0.1 to 48 hours.

Further, the compounds of the formula (C) can be prepared from acompound represented by the following formula (D):

wherein R² and R³¹ have the same meanings as those defined above. It ispreferable to convert a compound of the formula (D) into a compound ofthe formula (C) by oxidization in a solvent. Examples of the solventinclude acetic acid, trifluoroacetic acid, dichloromethane,1,2-dichloroethane, chloroform, acetonitrile, acetone,trichlorofluoromethane, benzene, and 1,4-dioxane, as well astert-butanol, water, and mixed solvents of these. Example of theoxidizing agent include hydrogen peroxide, sodium periodate, sodiumperborate, 3-chloroperbenzoic acid, ruthenium trichloride, and dimethyldioxylane, and the oxidizing agent is preferably used in an amount of 1to 20 moles based on the compound of the formula (D). The reaction ispreferably performed at a temperature of from room temperature to about100° C. The reaction time is preferably from 0.1 to 48 hours.

The compounds of the formula (A) wherein R¹ is hydrogen atom correspondto the compounds of the formula (D), and can be obtained as compounds ofthe formula (D). Among the compounds of the formula (D), the compoundsrepresented by the following formula (D-3):

wherein R²¹ represents any one of the atoms and groups defined for R²except for hydrogen atom and bromine atom, and R³¹ has the same meaningas that defined above, can be obtained from a compound represented bythe following formula (D-2):

wherein R³¹ has the same meaning as that defined above, by the followingvarious methods.

-   (i) The compounds of the formula (D-3) wherein R²¹ is fluorine atom    can be produced from a compound of the formula (D-2). The compound    of the formula (D-2) is preferably converted into a compound of the    formula (D-3) wherein R²¹ is fluorine atom by a halogen exchange    reaction using a fluorinating agent in an inert solvent. Examples of    the inert solvent include dimethylformamide, sulfolane,    N,N-dimethylformamide and the like. Examples of the fluorinating    agent include cesium fluoride, potassium fluoride, and    tetra(n-butyl)ammonium fluoride, and cesium fluoride is preferred.    The fluorinating agent is preferably used in an amount of 1 to 20    moles based on the compound of the formula (D-2). The reaction is    performed at a temperature of, for example, from room temperature to    200° C., preferably 80 to 150° C. The reaction time is preferably    from 0.1 to 48 hours.-   (ii) The compounds of the formula (D-3) wherein R²¹ is a C₁₋₆ alkyl    group, —(C₂₋₃ alkylene)O(G¹), —(C₂₋₃ alkylene)CO₂(G¹), a C₂₋₃    alkenyl group, a C₂₋₃ alkynyl group, or —(C₂₋₃ alkylene)SO₂(C₁₋₆    alkyl) can be produced from a compound of the formula (D-2). That    is, the compound of the formula (D-2) is preferably converted by    alkylation in an inert solvent. Examples of the inert solvent    include ether type solvents such as diethyl ether, tetrahydrofuran,    and 1,2-dimethoxyethane, acetonitrile, N,N-dimethylformamide, water,    and mixed solvents of these. The alkylation is preferably performed    by a reaction with an alkylating reagent in the presence of either    one of a nickel catalyst and palladium catalyst.

Examples of the nickel catalyst includedichloro(1,1′-bis(diphenylphosphino)ferrocene)nickel(II),dichloro(1,3-bis(diphenylphosphino)propane)nickel(II), andbis(acetylacetonato)nickel(II). Examples of the palladium catalystinclude dichloro(1,1′-bis(bisdiphenylphosphino)ferrocene)palladium(II),tetrakis(triphenylphosphine)palladium(0),dichloro(bis(triphenylphosphine))palladium(II), anddichloro(bis(benzonitrile))palladium(II). Examples of the alkylatingreagent include Grignard reagents including methyl iodide magnesium,methyl bromide magnesium and the like, organic zinc reagents including(ethoxycarbonylethyl)zinc bromide, (ethoxycarbonylmethyl)zinc bromideand the like, organic tin reagents including allyltributyltin,vinyltributyltin and the like, organic aluminum reagents includingvinyldiisobutylaluminum and the like, organic boron reagents includingalkylboron, alkenylboron and the like, organic lithium reagentsincluding methyllithium, vinyllithium and the like, organic copperreagents including alkylcopper, alkenylcopper and the like, organicsilicon reagents containing vinyltrimethylsilane,trimethylsilylacetylene and the like, and the like. The alkylatingreagent is preferably used in an amount of 1 to 20 moles, and thecatalyst is preferably used in an amount of 0.0001 to 1 mole, based onthe compound of the formula (D-2).

The reaction is performed at a temperature of, for example, from 0 to80° C., preferably from room temperature to 60° C., and the reactiontime is preferably from 0.1 to 48 hours. For example, if methyl iodidemagnesium or methyl bromide magnesium is used as the aforementionedalkylating reagent, a compound of the formula (D-3) wherein R²¹ ismethyl group can be prepared, if allyltributyltin is used, a compound ofthe formula (D-3) wherein R²¹ is allyl group can be obtained, if(ethoxycarbonylethyl)zinc bromide is used, a compound of the formula(D-3) wherein R²¹ is ethoxycarbonylethyl group can be prepared, if(ethoxycarbonylmethyl)zinc bromide is used, a compound of the formula(D-3) wherein R²¹ is ethoxycarbonylmethyl group can be prepared, ifvinyltributyltin is used, a compound of the formula (D-3) wherein R²¹ isvinyl group can be prepared, and if an alkylboron is used, a compound ofthe formula (D-3) wherein R²¹ is a corresponding alkyl group can beprepared.

Further, the preparation can be performed by a reaction with an alkenylcompound or alkynyl compound including acrylic esters, acrylonitrile,propargyl alcohol derivatives, end-acetylene derivatives and the like inthe presence of a base and copper(I) iodide or the like. As for thesereactions, Frank, W. C. et al., J. Org. Chem., 2947 (1978); Sonogashira,K. et al., Tetrahedron, 2303 (1984) and the like can be referred to.Examples of the base include triethylamine, diethylamine,diisopropylamine, sodium acetate, sodium hydroxide, lithium hydroxide,potassium carbonate, sodium tert-butoxide and the like. If protectionwith a protective group and subsequent deprotection are required duringthe aforementioned synthesis, the reactions can be properly performed byusing the aforementioned methods of Greene and Wuts, and Kocienski.

-   (iii) The compounds of the formula (D-3) wherein R²¹ is —N(G²)(G³),    —NH(C₂₋₃ alkylene)O(G¹), or —NH(C₂₋₃ alkylene)N(G²)(G³) can be    prepared from a compound of the formula (D-2). Examples of the    method include a method of aminating a compound of the formula (D-2)    in an inert solvent. The amination herein referred to means    conversion into unsubstituted —NH₂ and also conversion into an amino    which may have one or two substituents. Examples of the inert    solvent include ether type solvents such as tetrahydrofuran,    1,4-dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide,    N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, alcohol solvents    such as methanol and ethanol, water, and mixed solvents of these.    Examples of the aminating reagent include ammonia, primary amines    such as monomethylamine., and secondary amines such as    dimethylamine. The aminating reagent is preferably used in an amount    of 1 mole to large excess amount based on the compound of the    formula (D-2). The substitution reaction is preferably performed    under a heating condition of from room temperature to about 200° C.,    and the reaction time is preferably from 0.5 to 72 hours.

Alternatively, the coupling of a compound of the formula (D-2) with theaminating agent can be carried out in an inert solvent in the presenceof a palladium catalyst, phosphorus compound, and base (for example,according to Buchwald, S. L., J. Org. Chem., 1158 (2000); Buchwald, S.L., Organic Letters, 1101 (2000)). Examples of the inert solvent includeether type solvents such as tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane, toluene, and N,N-dimethylformamide. Examples of thepalladium catalyst include tris(dibenzylideneacetone)dipalladium(0),palladium(II) acetate and the like. Examples of the phosphorus compoundinclude 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, andtri(tert-butyl)phosphine. Further, examples of the base include sodiumtert-butoxide, cesium carbonate, potassium phosphate and the like.Examples of the aminating agent include lithium hexamethyldisilazide,primary amines such as methylamine, and secondary amines, such asdimethylamine. In the above reaction, when lithium hexamethyldisilazideis used, a compound of the formula (D-3) introduced with amino group asR²¹ can be obtained, when methylamine is used, a compound of the formula(D-3) introduced with methylamino group as R²¹ can be obtained, and whendimethylamine is used, a compound of the formula (D-3) introduced withdimethylamino group as R²¹ can be obtained, respectively.

-   (iv) The compounds of the formula (D-3) wherein R²¹ is a C₁₋₆    alkoxyl group, —O(C₂₋₃ alkylene)O(G¹), or —O(C₂₋₃ alkylene)SO₂(C₁₋₆    alkyl) can be prepared from a compound of the formula (D-2).    Preferred examples of the method include a method of etherifying a    compound of the formula (D-2) in an inert solvent. Examples of the    inert solvent include ether type solvents such as tetrahydrofuran,    1,4-dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide,    N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, water, and mixed    solvents of these. Examples of the etherification reagent include    metal alcoholates of lithium, sodium, potassium and the like (e.g.,    C₁₋₆ alkoxides such as methylate and ethylate, 2-hydroxyethylate,    2-methoxyethylate, 2-methanesulfonylethylate and the like are    included). The reaction is preferably performed in the presence of a    copper catalyst, and the reaction is preferably performed at a    temperature of from room temperature to about 180° C. The    etherification reagent is preferably used in an amount of from 1 to    20 moles. For example, when methylate is used as the metal    alcoholate, a compound of the formula (D-3) wherein methoxy group is    introduced as R²¹ is obtained, when ethylate is used, a compound of    the formula (D-3) wherein ethoxy group is introduced as R²¹ is    obtained, when 2-hydroxyethylate is used, a compound of the formula    (D-3) wherein 2-hydroxyethoxy group is introduced as R²¹ is    obtained, when 2-methoxyethylate is used, a compound of the formula    (D-3) wherein 2-methoxyethoxy group is introduced as R²¹ is    obtained, and when 2-methanesulfonylethylate is used, a compound of    the formula (D-3) wherein 2-methanesulfonylethoxy group is    introduced as R²¹ is obtained, respectively. The reaction time is    preferably from 0.1 to 72 hours.

Alternatively, a compound of the formula (D-3) wherein R²¹ is a C₁₋₆alkoxyl group, —O(C₂₋₃ alkylene)O(G¹), or —O(C₂₋₃ alkylene)SO₂(C₁₋₆alkyl) can also be obtained by reacting a compound of the formula (D-2)with an etherification agent in the presence of a palladium catalyst,phosphorus compound, and base in an inert solvent (for example,according to Buchwald, S. L., J. Org. Chem., 1158 (2000); Buchwald, S.L., Organic Letters, 1101 (2000)). Examples of the inert solvent includeether type solvents such as tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxy ethane, and toluene. Examples of the palladium catalystinclude palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0),palladium(II) acetate and the like. Examples of the phosphorus compoundinclude 2-(di-tert-butylphosphino)biphenyl,2-(di-tert-butylphosphino)-1,1′-binaphthyl, and2-(di-tert-butylphosphino)-2′-dimethylamino-1,1′-binaphthyl. Further,examples of the base include sodium tert-butoxide, potassiumtert-butoxide, cesium carbonate, potassium phosphate and the like.Examples of the etherification agent include, for example, alcohols suchas methanol, ethanol, ethylene glycol, and methanesulfonylethanol. Inthe above reaction, depending on the alcohol used, a compound of theformula (D-3) in which R²¹ is converted into a corresponding alkoxylgroup can be obtained. When protection with a protective group andsubsequent deprotection are required during the aforementionedsynthesis, the reaction can be appropriately performed by using theaforementioned methods of Greene and Wuts, and Kocienski.

-   (v) The compounds of the formula (D-3) wherein R²¹ is —S(C₁₋₆ alkyl)    can be prepared from a compound of the formula (D-2). Preferred    examples of the method include a method of alkylthionating a    compound of the formula (D-2) in an inert solvent. Examples of the    inert solvent include, for example, tetrahydrofuran, 1,4-dioxane,    1,2- dimethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone,    dimethyl sulfoxide, sulfolane, methanol, ethanol, propanol, water,    and a mixed solvent of these. Examples of the alkylthionating    reagent include, for example, metal thiolates of lithium, sodium,    potassium and the like (e.g., C₁₋₆ alkyl thiolates such as methyl    thiolate and ethyl thiolate are included). The alkylthionating    reagent is preferably used 1 to 20 moles, and the reaction is    preferably performed at a temperature of from room temperature to    about 180° C. The reaction time is preferably from 0.1 to 72 hours.

Further, the compounds of the formula (D-3) wherein R²¹ 0is —SO(C₁₋₆alkyl) can be prepared from a compound of the formula (D-3) wherein R²¹is —S(C₁₋₆ alkyl). Preferred examples of the method include a method ofoxidizing a compound of the formula (D-3) wherein R²¹ is —S(C₁₋₆ alkyl)in an inert solvent. Examples of the inert solvent include, for example,dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile,tert-butanol, acetic acid, trifluoroacetic acid, water, and mixedsolvents of these. Examples of the oxidizing agent, which is used in anamount of 0.3 to 2 equivalences, include sodium metaperiodate,3-chloroperbenzoic acid, and hydrogen peroxide. The oxidizing agent ispreferably used in an amount of 0.3 to 2 moles based on the startingcompound, and the reaction time is preferably from 0.1 to 48 hours.

Further, the compounds of the formula (D-3) wherein R²¹ is —SO₂(C₁₋₆alkyl) can be produced from a compound of the formula (D-3) wherein R²¹is —S(C₁₋₆ alkyl). Preferred examples of the method include a method ofoxidizing a compound of the formula (D-3) wherein R²¹ is —S(C₁₋₆ alkyl)in an inert solvent. Although the reaction can be performed by using aninert solvent and oxidizing agent similar to those used in theaforementioned oxidation step, the oxidizing agent is preferably used inan amount of 2 moles or more based on the starting compound.Alternatively, the compounds of the formula (D-3) wherein R²¹ is—SO₂(C₁₋₆ alkyl) can be prepared from a compound of the formula (D-2).Preferred examples of the method include a method of sulfonylating acompound of the formula (D-2) in an inert solvent. Examples of the inertsolvent include, for example, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone,dimethyl sulfoxide, sulfolane, methanol, ethanol, propanol, water, and amixed solvents of these. Examples of the slufonylating agent includesodium and potassium (C₁₋₆ alkyl)sulfinates, and by using the agent, acompound of the formula (D-2) can be converted into a compound of theformula (D-3) wherein R²¹ is a corresponding C₁₋₆ alkylsulfonyl group.The reaction is preferably performed at a temperature of from roomtemperature to about 180° C. The reaction time is preferably from 0.1 to48 hours. When protection with a protective group and subsequentdeprotection are required during the aforementioned synthesis, reactionscan be properly performed by using the aforementioned methods of Greeneand Wuts, and Kocienski.

-   (vi) The compounds of the formula (D-3) wherein R²¹ is cyano group    can be produced from a compound of the formula (D-2). That is, a    preferred example of the production method is a method of cyanating    a compound of the formula (D-2) by using an appropriate cyanating    agent in an inert solvent (e.g., according to Newman, M. S. et    al., J. Org. Chem. 2525 (1961)). Examples of the inert solvent    include, for example, solvents such as tetrahydrofuran, 1,4-dioxane,    1,2-dimethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone,    dimethyl sulfoxide, sulfolane, methanol, ethanol, and propanol,    water, and mixed solvents of these. Examples of the cyanating agent    include copper(I) cyanide, sodium cyanide, potassium cyanide, zinc    cyanide, silver cyanide, potassium ferrocyanide (II) and the like.    The cyanating agent is preferably used in an amount of 1 to 20    moles, and the reaction is preferably performed at a temperature of    from room temperature to about 180° C.

Alternatively, the coupling of the compound of the formula (D-3) withthe cyanating agent can be carried out in an inert solvent in thepresence of a catalyst and a phosphorus compound (e.g., according toMaligres, P. E. et al., Tetrahedron Letters, 8193 (1999)). Examples ofthe catalyst includedichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II),tetrakis(triphenylphosphine)palladium(0),dichloro(bis(triphenylphosphine))palladium(II),dichloro(bis(benzonitrile))palladium(II),tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate,dichloro(1,1′-bis(diphenylphosphino)ferrocene)nickel(II), dichloro(1,3-bis(diphenylphosphino)propane)nickel(II),dibromo(bis(triphenylphosphine))nickel(II),bis(acetylacetonato)nickel(II) and the like, and examples of thephosphorus compound include, for example,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,1′-bis(diphenylphosphino)ferrocene, xantphos, andtri(tert-butyl)phosphine. In the aforementioned synthesis, if protectionwith a protective group and subsequent deprotection are required,reactions can be properly performed by using the methods of Greene andWuts, and Kocienski mentioned above.

The compounds of the formula (D) wherein R² is hydrogen atom, which isrepresented by the following formula (D-1):

wherein R³¹ has the same meaning as that defined above, can be producedby the following method.

The compounds represented by the following formula (D-1-1):

wherein A¹, A¹¹, A², A²¹, A³, X, and PG have the same meanings as thosedefined above, which correspond to the compounds of the formula (D-1)wherein R³¹ is a group represented by the formula (a-1), can be preparedfrom commercially available 5-hydroxyisoquinoline (Aldrich) and anN-protected amino alcohol represented by the following formula (E-11):

wherein A¹, A¹¹, A², A²¹, A³, X, and PG have the same meanings as thosedefined above, which is commercially available or can be prepared.Examples of the reaction method include a method of carrying out thereaction in an inert solvent in the presence of a phosphorus reagent,and azo compound (e.g., Tsunoda et al., Chemistry Letters, 539 (1994);Mitsunobu, O., Synthesis, 1 (1981)). Examples of the inert solventinclude, for example, tetrahydrofuran, toluene, and dichloromethane.Examples of the phosphorus reagent include, for example,triphenylphosphine and tri(n-butyl)phosphine. Examples of the azocompound include, for example, diethyl azodicarboxylate, di(isopropyl)azodicarboxylate and 1,1′-azobis(N,N-dimethylformamide). The amounts ofthe phosphorus reagent, azo compound, and N-protected amino alcohol(E-11) may be the same or different, and they are used in amounts of 1to 6 moles, preferably 2 to 4 moles, based on 5-hydroxyisoquinoline. Thereaction temperature is about −10 to 80° C., preferably about 0 to 60°C.

The compounds represented by the following formula (D-1-2):

wherein A¹, A¹¹, A², A²¹, A³, X, and PG have the same meanings as thosedefined above, which correspond to the compounds represented by theformula (D-1) wherein R³¹ is a group represented by the formula (a-2)provided that R⁴ is hydrogen atom, can be prepared from commerciallyavailable 5-aminoisoquinoline (Aldrich) and an N-protected aminocarbonylcompound represented by the following formula (F-11):

wherein A², A²¹, A³, and PG have the same meanings as those definedabove, and Z represents a group represented by the following formula(F-11-1), (F-11-2), (F-11-3), or (F-11-4):

wherein A¹, A¹¹, A⁵, A⁶, and A⁶¹ have the same meanings as those definedabove, and n is 1 or 2, which is commercially available or can beprepared. Examples of the reaction method include a method of performingreduction amination without solvent or in an inert solvent. Examples ofthe inert solvent include, for example, dichloromethane,1,2-dichloroethane, and toluene, and a dehydrating agent may be usedtogether. Examples of the dehydrating agent include, for example,titanium isopropoxide. Preferably, dehydration condensation is performedunder the aforementioned conditions to form a Schiff base, then theaforementioned inert solvent is removed, and the inert solvent is newlyadded to perform the reduction. Examples of the reducing agent include,for example, sodium borohydride and sodium cyanoborohydride. Examples ofthe inert solvent for the reduction include alcohols such as methanol.The reducing agent is preferably used in an amount of about 1 to 10moles based on the compound of the formula (F-11). The reaction ispreferably performed at 0° C. to 80° C. The reaction time is preferablyfrom 0.1 to 72 hours.

The compounds of the formula (1) wherein A³¹ is a C₁₋₆ alkyl groupsubstituted with hydroxyl group can also be prepared by subjecting acompound corresponding to a compound of the formula (F-11) which issubstituted with a C₁₋₆ alkyl group substituted with a protectedhydroxyl group instead of the substitution of PG to a series of stepssimilar to those explained in the present specification. That is, insuch a reaction route, R³ in the formula (A) is a group represented bythe formula (a-1) or formula (a-2), and the objective compound isprepared via a compound analogous to the corresponding compound of theformula (A), in which a C₁₋₆ alkyl group substituted with a protectedhydroxyl group substitutes instead of the substitution of PG.

Further, the compounds represented by the following formula (D-1-3):

wherein A¹, A¹¹, A², A²¹, A³, X, R⁴, and PG have the same meanings asthose defined above, which correspond to the compounds represented bythe formula (D-1) in which R³¹ represents a group represented by theformula (a-2), can be prepared from commercially available5-bromoisoquinoline and an N-protected diamine represented by thefollowing formula (F-12):

wherein A¹, A¹¹, A², A²¹, A³, X, R⁴, and PG have the same meanings asthose defined above. Examples of the reaction method include a method ofcarrying out the reaction in an inert solvent in the presence of apalladium catalyst, phosphorus compound, and base (for example,according to Buchwald, S. L., J. Org. Chem., 1158 (2000); Buchwald, S.L., Organic Letters, 1101 (2000)). Examples of the inert solventinclude, for example, 1,4-dioxane, toluene, tetrahydrofuran, anddimethoxyethane. Examples of the palladium catalyst include, forexample, tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. Examples of the phosphorus compound include, for example,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, andtri(tert-butyl)phosphine. Examples of the base include, for example,sodium tert-butoxide, cesium carbonate, and potassium phosphate. Thereaction is performed at a temperature of, for example, from 20 to 120°C.

The compounds represented by the following formula (D-1-4):

wherein A⁴, R⁵, Y, and PG have the same meanings as those defined above,which correspond to the compounds represented by the formula (D-1) inwhich R³¹ is a group represented by the formula (a-3), can be preparedfrom a compound represented by the following formula (J-1):

wherein A⁴, Y, and PG have the same meanings as those defined above, andan alcohol represented by the following formula (H-1):R⁵—OH  (H-1)wherein R⁵ has the same meanings as that defined above. Examples of thereaction method include a method of carrying out the reaction in aninert solvent in the presence of a phosphorus reagent, and azo compound(for example, Tsunoda et al., Chemistry Letters, 539 (1994) orMitsunobu, O., Synthesis, 1 (1981)). Examples of the inert solventinclude, for example, tetrahydrofuran, toluene, benzene, anddichloromethane. Examples of the phosphorus reagent include, forexample, triphenylphosphine, and tributylphosphine. Examples of the azocompound include, for example, diethyl azodicarboxylate, di(isopropyl)azodicarboxylate, and 1,1′-azobis(N,N-dimethylformamide). The phosphorusreagent, the azo compound, and the alcohol of the formula (H-1) can beused in amounts of 1 to 6 moles, preferably 1 to 4 moles, based on thecompound of the formula (J-1), and the reaction temperature is about −10to 80° C., preferably about 0 to 60° C.

The compounds of the formula (J-1) can be prepared from a knowncompound, 5-isoquinolinesulfonyl chloride (Japanese Patent UnexaminedPublication (Kokai) Nos. 57-156463, 57-200366, 58-121278, 58-121279,59-93054, and 63-2980), which is also commercially available, and anN-protected diamine represented by the following formula (K-1):

wherein A⁴, Y, and PG have the same meanings as those defined above, bycoupling them in an inert solvent in the presence of a base. Examples ofthe inert solvent include, for example, halogenated hydrocarbons such asdichloromethane, chloroform, and 1,2-dichloroethane, and acetonitrile.Examples of the base include, for example, organic bases such astriethylamine, N,N-diisopropylethylamine, and pyridine, and inorganicbases such as potassium carbonate, and sodium hydrogencarbonate. Thebase and the N-protected diamine of the formula (K-1) are usually usedin amounts of 1 to 6 moles, preferably 1.1 to 2.2 moles, based on5-isoquinolinesulfonyl chloride, and the reaction temperature is about−10 to 40° C., preferably about 0 to 30° C. The reaction time ispreferably from 0.1 to 48 hours.

The compounds represented by the following formula (D-2-1):

wherein A¹, A¹¹, A², A²¹, A³, X, and PG have the same meanings as thosedefined above, which correspond to the compounds of the formula (D-2) inwhich R³¹ represents a group represented by the formula (a-1), can beprepared from 4-bromo-5-hydroxyisoquinoline represented by the followingformula (E-2):

and an N-protected amino alcohol of the formula (E-11). The reaction canbe carried out under the same conditions as those of the method ofpreparing the compounds of the formula (D-1-1) from5-hydroxyisoquinoline and an N-protected amino alcohol of the formula(E-11), except that 5-hydroxyisoquinoline is changed to4-bromo-5-hydroxyisoquinoline of the formula (E-2).

The compound represented by the formula (E-2) can be prepared from4-bromo-5-aminoisoquinoline (Reference Example 1) represented by thefollowing formula (F-2):

The compound of the formula (F-2) is reacted with sodium nitrite inhydrochloric acid, and thereby converted into a diazonium salt. Sodiumnitrite is preferably used in an amount of 1 to 2 moles based on thecompound of the formula (F-2). The reaction is performed at −30 to 10°C., preferably −20 to 0° C. The time for formation of the diazonium saltis preferably from 0.1 to 4 hours. Then, for example, the diazonium saltis converted into the compound of the formula (E-2) by hydroxylation inaqueous sulfuric acid. The reaction temperature in the aqueous sulfuricacid is preferably from room temperature to 100° C. The time for thehydroxylation is preferably from 2 to 48 hours.

Further, the compounds represented by the following formula (D-2-2):

wherein A¹, A¹¹, A², A²¹, A³, X, and PG have the same meanings as thosedefined above, which correspond to the compounds represented by theformula (D-2) in which R³¹ represents a group represented by the formula(a-2) provided that R⁴ is hydrogen atom, can be prepared from4-bromo-5-aminoisoquinoline of the formula (F-2), and an N-protectedaminocarbonyl compound of the formula (F-11). The reaction can becarried out under the same conditions as those of the method ofpreparing the compounds of the formula (D-1-2) from 5-aminoisoquinoline,and the N-protected aminocarbonyl compound of the formula (F-11), exceptthat 5-aminoisoquinoline is changed to 4-bromo-5-hydroxyisoquinoline ofthe formula (F-2).

The compounds represented by the following formula (D-2-4):

wherein A⁴, R⁵, Y, and PG have the same meanings as those defined above,which correspond to the compounds of the formula (D-2) in which R³¹represents a group represented by the formula (a-3), can be preparedfrom a compound represented by the following formula (J-2):

wherein A⁴, Y, and PG have the same meanings as those defined above, andan alcohol of the formula (H-1). The reaction can be carried out underthe same conditions as the method of preparing the compounds of theformula (D-1-4) from a compound of the formula (J-1), and an alcohol ofthe formula (H-1) except that the compound of the formula (J-1) ischanged to a compound of the formula (J-2).

The compounds of the formula (J-2) can be produced from a knowncompound, 4-bromo-5-isoquinolinesulfonyl chloride (Japanese Patent No.2763791), and an N-protected diamine of the formula (K-1), which iscommercially available or can be prepared, by coupling them in an inertsolvent in the presence of a base. The reaction can be carried out underthe same conditions as those in the method of preparing the compounds ofthe formula (J-1) from 5-isoquinolinesulfonyl chloride, and anN-protected diamine.of the formula (K-1) except that5-isoquinolinesulfonyl chloride is changed to4-bromo-5-isoquinolinesulfonyl chloride.

The compounds represented by the following formula (B-1):

wherein A⁴, R⁵, Y, and PG have the same meanings as those defined above,which correspond to the compounds of the formula (B) in which R² ishydrogen atom, and R³¹ is a group represented by the formula (a-3), canbe prepared from a compound represented by the following formula (M):

wherein A⁴, Y, and PG have the same meanings as those defined above, andan alcohol of the formula (H-1). The reaction can be carried out underthe same conditions as those in the method of preparing the compounds ofthe formula (D-1-4) from a compound of the formula (J-1), and an alcoholof the formula (H-1) except that the compound of the formula (J-1) ischanged to a compound of the formula (M).

The compounds of the formula (M) can be produced from a known compound,1-chloro-5-isoquinolinesulfonyl chloride (Japanese Patent UnexaminedPublication (Kokai) No. 63-2980), and an N-protected diamine of theformula (K-1) by coupling them in an inert solvent in the presence of abase. The reaction can be carried out under the same conditions as thosein the method of preparing the compounds of the formula (J-1) from5-isoquinolinesulfonyl chloride, and an N-protected diamine of theformula (K-1) except that 5-isoquinolinesulfonyl chloride is changedinto 1-chloro-5-isoquinolinesulfonyl chloride.

The compounds represented by the following formula (A-1):

wherein A⁴, R⁵, Y, and PG have the same meanings as those defined above,which correspond to the compound of the formula (A) wherein R¹ is aminogroup, R² is hydrogen atom, and R³¹ is a group represented by theformula (a-3), can be prepared from a compound represented by thefollowing formula (P):

wherein A⁴, Y, and PG have the same meanings as those defined above, andan alcohol of the formula (H-1). The reaction can be carried out underthe same conditions as those in the method of preparing the compound ofthe formula (D-1-4) from a compound of the formula (J-1), and an alcoholof the formula (H-1) except that the compound of the formula (J-1) ischanged to a compound of the formula (P).

The compounds of the formula (P) can be produced by aminating a compoundof the formula (M). Examples of the reaction method include a method ofattaining the conversion by adding aqueous ammonia in an inert solvent.Examples of the inert solvent include 1,4-dioxane, and tetrahydrofuran,and aqueous ammonia having a concentration of 20% or more, for example,may be used. The reaction is carried out at room temperature to 200° C.,preferably 100 to 150° C. The reaction time is preferably from 0.5 to 72hours.

The compounds of the present invention represented by the aforementionedformula (1) have cell movement inhibitory actions on the basis ofinhibition against phosphorylation of the myosin regulatory light chainin the cells, and are useful as active ingredients of medicaments. Amongthe cell movement inhibitory actions of the compounds of the presentinvention, the cell contraction inhibitory action can be confirmed bymeasuring vasoconstriction inhibitory activity, intraocular pressuredepression activity, or the like. The action to regulate change of cellmorphology can be confirmed by, for example, measuring extension ofneural axes of nerve cells, or the like. The inhibitory action on cellmigration (the action will be abbreviated as “cell migration inhibitoryaction”) can be confirmed by measuring neutrophil migration inhibitoryactivity, respiratory tract inflammation suppression activity, or thelike. The cell release inhibitory action can be confirmed by measuringthe chemical mediator releasing amount from neutrophils. The cellaggregation inhibitory action can be confirmed by measuring plateletaggregation inhibitory activity, or the like. Further, the apoptosisinhibitory action can be confirmed by giving stimulation to induceapoptosis to cells and then measuring viability of the cells oroccurring frequencies of morphological changes characteristic toapoptosis such as nuclear condensation, nuclear fragmentation, andblebbing of cells. However, since the cell movement inhibitory actionson the basis of the inhibition of phosphorylation of the myosinregulatory light chain in the cells are known to be associated withvarious biological actions as described in the section of related art inthe specification, the cell movement inhibitory actions must beconstrued in their broadest sense including the aforementioned cellcontraction inhibitory action, action to regulate change of cellmorphology, cell migration inhibitory action, cell release inhibitoryaction, cell aggregation inhibitory action, and apoptosis inhibitoryaction.

For example, the compounds of the present invention represented by theaforementioned formula (1) have an inhibitory activity againstphosphorylation of the myosin regulatory light chain (see, Test Example1 of the specification), vasoconstriction inhibitory activity (see, TestExample 2 in the specification), respiratory tract constrictioninhibitory activity (see, Test Example 3 in the specification),intraocular pressure reducing activity (see, Test Example 4 in thespecification), neutrophil migration inhibitory activity (see, TestExample 5 in the specification), and respiratory tract inflammationsuppression activity (see, Test Example 6 in the specification).Further, as demonstrated by the test examples, the compounds representedby the aforementioned formula (1) have notably higher vasoconstrictioninhibitory activity, respiratory tract constriction inhibitory activity,intraocular pressure reducing activity, neutrophil migration inhibitoryactivity, and respiratory tract inflammation suppression activity ascompared with the conventional isoquinoline compounds. Therefore, thecompounds represented by the aforementioned formula (1) and saltsthereof are useful as active ingredients of medicaments for prophylacticand/or therapeutic treatment of diseases relating to contraction ofvarious cells, diseases relating to morphological change of variouscells, diseases relating to migration of various cells, diseasesrelating to release of various cells, diseases relating to aggregationof various cells, and/or diseases relating to apoptosis of variouscells, and the like.

Although it is not intended to be bound by any specific theory, actionmechanism of the compounds of the present invention represented by theaforementioned general formula (1) can be presumed as follows. It isknown that increase of the amount of phosphorylated myosin regulatorylight chain activates the actomyosin system, which is a movementapparatus of cytoskeleton, and activates cell movements. Therefore, itis considered that the phosphorylation reaction of myosin regulatorylight chain is important for cell movements (Kamm, K., et al., Annu.Rev. Physiol., 51, pp.299-313, 1989; Schmidt, J. T. et al., J.Neurobiol., 52(3), pp.175-188, 2002; Niggli, V., FEBS Lett., 445,pp.69-72, 1999; Itoh, K., et al., Biochim. Biophys. Acta., 1136,pp.52-56, 1992; Kitani, S., et al., Biochem. Biophys. Res. Commun., 183,pp.48-54, 1992; Mills, J. C., J. Cell Biol., 140(3), pp.627-636, 1998).Measurement of the amount of phosphorylated myosin regulatory lightchain in the cells revealed that the compounds represented by theaforementioned formula (1) decrease the amount of phosphorylated myosinregulatory light chain in the cells (refer to Test Example 1).

It is known that the amount of phosphorylated myosin regulatory lightchain in the cells is determined by activated states of two reactionroutes including Reaction route 1 and Reaction route 2 described below(Fukata, Y., et al., Trends Pharmacol. Sci., 22, pp.32-39, 2001).

<Reaction Route 1>

-   Increase of intracellular calcium concentration→Activation of myosin    light chain kinase→Increase of amount of phosphorylated myosin    regulatory light chain    <Reaction Route 2>-   Activation of low molecular weight G protein Rho→Activation of Rho    kinase→Phosphorylation (inactivation) of myosin phosphatase→Increase    of amount of phosphorylated myosin regulatory light chain

It is considered that a compound that inhibits Reaction route 1 and/orReaction route 2 mentioned above has an activity for decreasing theamount of phosphorylated myosin regulatory light chain. In order toestimate whether either or both of Reaction route 1 and Reaction route 2mentioned above are the target site for the compounds of the presentinvention represented by the aforementioned formula (1), effects of thecompounds of the present invention represented by the aforementionedformula (1) on increase of intracellular calcium concentration andactivity of myosin light chain kinase were examined. As a result, it wasfound that the compounds of the present invention gave no influence onthe increase of intracellular calcium concentration (see, Test Example7), and did not inhibit the myosin light chain kinase activity (see,Test Example 8). Therefore, it is presumed that the compounds of theformula (1) according to the present invention do not inhibit Reactionroute 1 mentioned above, but inhibit Reaction route 2 mentioned above todecrease the amount of phosphorylated myosin regulatory light chain.Thus, the compounds of the present invention can be used as inhibitorsof the Rho/Rho kinase pathway. The inhibition of Reaction route 2mentioned above by the compounds of the present invention represented bythe aforementioned formula (1) can be confirmed by measuring theinhibitory activity for the Rho kinase activity, or alternatively, bymeasuring the inhibitory activity for the phosphorylation reaction ofmyosin phosphatase.

The activity of Rho kinase can be measured by the method disclosed inWO01/56988. More specifically, ATP (γ³²P-ATP) is added to a substrate(Ribosomal S6 kinase substrate) together with a commercially availableRho kinase (Upstate) to start the enzymatic reaction and phosphorylatethe substrate. The substrate is adsorbed on filter paper, and ATP iswashed off with the phosphate buffer. Then, the amount of thephosphorylated substrate is measured by using a liquid scintillationcounter. The inhibitory activity of the compounds of the presentinvention represented by the aforementioned formula (1) for the Rhokinase activity can be determined by adding the compounds beforestarting the enzymatic reaction, and measuring suppression of thephosphorylation amount of the substrate. The phosphorylation reaction ofmyosin phosphatase can be measured by, for example, using an antibodyspecifically recognizing the phosphorylated myosin phosphatase (Feng, J.et al., J. Biol. Chem., 274, pp.37385-37390, 1999). More specifically,proteins including myosin phosphatase are extracted from a tissue,subjected to electrophoresis on acrylamide gel, and transferred to anitrocellulose membrane. The proteins are reacted with antibodiesspecifically recognizing phosphorylated myosin phosphatase to detect theamount of phosphorylated myosin phosphatase. The inhibitory activity onthe phosphorylation reaction of myosin phosphatase can be determined byadding the compounds before starting the extraction from the tissue, andmeasuring suppression of the phosphorylation amount of the myosinphosphatase.

It is considered that the compounds of the present invention representedby the aforementioned formula (1) inhibit the Rho/Rho kinase pathway,which is Reaction route 2 mentioned above, and exhibit more potent cellcontraction inhibitory activity and cell migration inhibitory activitycompared with the conventional isoquinoline compounds. It is known thatthe Rho/Rho kinase route plays an important role for cell contractionand cell migration. Other than the above, it has been reported that theRho/Rho kinase pathway controls a variety of cellular functions such asaggregation, release, production, division, and gene expression invarious cell lines (Fukata, Y., et al., Trends in PharmacologicalSciences, 22, pp.32-39, 2001; Murata T., et al., J. Hepatotol., 35,pp.474-481, 2001; Ohnaka, K., et al., Biochem. Biophys. Res. Commun.,287, pp.337-342, 2001; Arakawa, Y. et al., BIO Clinica, 17(13),pp.26-28, 2002). Therefore, the compounds of the present invention whichinhibit the Rho/Rho kinase pathway exhibit, based on that effect, morepotent cell contraction inhibitory activity (Test Examples 2, 3, and 4),cell morphology change regulating activity, cell migration inhibitoryactivity (Test Examples 5, and 6), cell release inhibitory activity,cell aggregation inhibitory activity, cell apoptosis inhibitoryactivity, and/or activity of regulating gene expression in cellscompared with the conventional isoquinoline compounds, and are useful asactive ingredients of medicaments for prophylactic and/or therapeutictreatment of diseases relating to contraction of various cells, diseasesrelating to morphological change of various cells, diseases relating tomigration of various cells, diseases relating to release from variouscells, diseases relating to aggregation of various cells, diseasesrelating to apoptosis of various cells, and/or diseases relating toabnormal gene expression in various cells (Jikken Igaku (ExperimentalMedicine) Vol. 17, 7, 1999).

Examples of the diseases relating to contraction of various cellsinclude, for example, as those relating to vascular smooth muscles,hypertension, arteriosclerosis, cerebral circulatory disturbance, brainfunction disorder with the aforementioned disease (mental disorder,memory disorder, dementia, delirium, poriomania, dyskinesia and thelike), dizziness, cardiac diseases, pokkuri-byou (sudden death),disturbances of peripheral circulation, disturbances of retinalcirculation, renal failure and the like, as those relating to airwaysmooth muscles, asthma, acute respiratory distress syndrome (ARDS),pulmonary emphysema, peripheral respiratory tract disease, chronicbronchitis, chronic obstructive pulmonary disease (COPD), and the like(Ueki, J. et al., Gendai Iryo (Contemporary Medical Care), Vol.34, No.9,pp.87-92, 2002), as those relating to digestive tract smooth muscles,vomiting, chronic gastritis, reflux esophagitis, irritable bowelsyndrome and the like, as those relating to smooth muscle cells existingin eyes, glaucoma, and the like, as those relating to smooth muscles ofbladder and urethra, dysuria, pollakiuria, incontinence and the like, asthose relating to smooth muscles of uterus, gestational toxicosis,threatened premature delivery, abortion and the like, and as thoserelating to smooth muscles of penis, erectile dysfunction is known.However, the diseases are not limited to the aforementioned examples.

More precisely, examples of hypertension include essential hypertension,renal hypertension, renovascular hypertension, hypertension duringpregnancy, endocrine hypertension, cardiovascular hypertension,neurogenic hypertension, iatrogenic hypertension, pulmonary hypertensionand the like, and examples of arteriosclerosis include those in whichpathological change is observed in major arteries in whole body such ascoronary artery, aorta abdominalis, renal artery, carotid artery,ophthalmic artery, and cerebral artery. Examples of cerebral circulatorydisturbance include cerebral thrombosis, cerebral infarction, cerebralhemorrhage, transient brain ischemic attack, hypertensiveencephalopathy, cerebral arteriosclerosis, subdural hemorrhage, epiduralhemorrhage, subarachnoid hemorrhage, brain hypoxia, cerebral edema,encephalitis, brain tumor, head injury, mental disorder, metabolicintoxication, drug intoxication, transient aphyxia, deep anesthesia inoperation and the like. The cardiac diseases include congestive heartfailure, acute myocardial infarction, previous myocardial infarction,subendocardial infarction, right ventricular infarction, atypicalmyocardial infarction, ischemic cardiomyopathy, variant angina pectoris,stable angina, effort angina, coronary vasospasm, postinfarction angina,unstable angina pectoris, arrhythmia, and acute cardiac death.

The peripheral circulatory disturbances include aortic diseases such asBuerger's disease, arteriosclerotic obliteration, and Raynaud'ssyndrome, venous diseases such as venous thrombosis andthrombophlebitis, hyperviscosity syndrome, frostbite and chilblain,psychoesthesia and hypnagogic disturbance due to feeling of cold,bedsore, cleft, and alopecia. Examples of the retinal circulatorydisturbances include retinal vascular obstruction caused thereby,arteriosclerotic retinopathy, vasospastic retinopathy, hypertonicfundus, hypertensive retinopathy, renal retinopathy, hypertensiveneuroretinopathy, diabetic retinopathy and the like. Glaucoma includesprimary glaucoma, secondary glaucoma, developmental glaucoma, childhoodsecondary glaucoma and the like, as well as more narrowly classifiedtypes of the foregoings, including primary open-angle glaucoma, primaryangle-closure glaucoma, mixed-type glaucoma, ocular hypertension, andthe like (Japanese Journal of Ophthalmology, vol. 107, No. 3, 2003). Theurinary disturbances include dysuria, bladder neck contracture, bladderneck occlusion, urethral syndrome, detrusor sphincter dyssynergia,unstable bladder, chronic prostatitis, chronic cystitis, prostate pain,Hinman's syndrome, Fowler's syndrome, psychogenic dysuria, drug-induceddysuria, dysuria with aging and the like. The erectile dysfunctioninclude organic erectile dysfunction accompanying diseases of diabetesmellitus, arteriosclerosis, hypertension, multiple-sclerotic cardiacdiseases, hyperlipidemia, depression and the like, functional erectiledysfunction, erectile dysfunction with aging, and erectile dysfunctionafter spinal cord injury or radical prostatectomy.

Examples of the diseases relating to morphological change of variouscells include, for example, various nerve dysfunctions as those relatingto nerve cells. As the nerve dysfunctions, for example, neural damagescaused by trauma (spinal cord injury and the like), neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease and diabeticretinopathy and the like can be exemplified

Examples of the diseases relating to migration of various cells include,for example, as those relating to cancer cells, infiltration andmetastasis of cancer. Examples of those relating to vascular endothelialcells include angiogenesis. Examples of those relating to leukocytesinclude bacterial infection, allergic hypersensitive diseases (e.g.,bronchial asthma, atopic dermatitis, pollinosis, anaphylactic shock andthe like), collagen diseases (e.g., rheumatoid arthritis, systemic lupuserythematodes, multiple sclerosis, Sjogren's disease and the like),angiitis, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn'sdisease and the like), ischemic reperfusion injury of visceral organs,traumatic spinal cord injury, pneumonia, hepatitis, nephritis,pancreatitis, otitis media, sinusitis, arthritis (for example,osteoarthritis, gout and the like can be exemplified), fibrosis, AIDS,adult T-cell leukemia, rejection after organ transplantation (graftversus host reaction), vascular restenosis, and endotoxin shock. Exampleof the cancer include myelocytic leukemia, lymphatic leukemia, gastriccancer, carcinoma of the colon and rectum, lung cancer, pancreaticcarcinoma, hepatocellular carcinoma, carcinoma of the esophagus, ovariancancer, breast cancer, skin cancer, head and neck cancer, cancer of thetesticles, neuroblastoma, urinary tract epithelial cancer, multiplemyeloma, carcinoma uteri, melanoma, brain tumor and the like. Examplesof hepatitis include hepatitis by virus infection (e.g., hepatitis B,hepatitis C and the like), and alcoholic hepatitis. Examples of thepneumonia include chronic obstructive pulmonary disease (COPD) andinterstitial pneumonia, which may shift to fibrosis. Examples ofnephritis include chronic nephritic syndrome, asymptomatic proteinuria,acute nephritic syndrome, nephrotic syndrome, IgA nephropathy,pyelonephritis, glomerulonephritis and the like. Fibrosis includechronic pathological changes characterized by excess deposition ofconnective tissue proteins in lung, skin, heart, liver, pancreas, kidneyand the like. The major pathological conditions are pulmonary fibrosis,hepatic fibrosis, and skin fibrosis. However, fibrosis is not limited tothese examples. In hepatic fibrosis, viral hepatitis progresses byinfection of, in particular, hepatitis B virus or hepatitis C virus,thus hepatic cells cause necrosis, and thereby fibrosis progresses,which means macronodular hepatic cirrhosis. Further, hepatic fibrosisalso includes micronodular hepatic cirrhosis caused by progress ofalcoholic hepatitis.

Examples of diseases relating to release of various cells include, asthose relating to leukocytes, for example, allergic diseases.

Examples of the allergic diseases include asthma, atopic dermatitis,allergic conjunctivitis, allergic arthritis, allergic rhinitis, allergicpharyngitis and the like.

Examples of the diseases relating to aggregation of various cellsinclude, as those relating to platelets, for example, thrombosis.

Thrombosis include the aforementioned circulatory disturbances of majorarteries, major veins and peripheral arteries and veins in whole body,as well as shock caused by hemorrhage, drug intoxication, or endotoxin,disseminated intravascular coagulation (DIC) following it, and multipleorgan failure (MOF).

Examples of the diseases relating to apoptosis of various cells include,as those relating to nerves, for example, neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, diabetic peripheralneuropathy, retinopathy, amyotrophic lateral sclerosis due to cerebralischemia, pigmented retinitis, and cerebellar degeneration, andglaucoma. Examples of glaucoma are mentioned above. AIDS, and fulminanthepatites are examples of disease relating to viruses, chronic heartfailure due to myocardial ischemia is an example of diseases relating tosmooth muscles, myelodysplasia, aplastic anemia, sideroblastic anemia,and graft-versus-host disease (GVHD) after organ transplantation areexamples of diseases relating to blood, arthrosteitis, and osteoporosisis an example of diseases relating to bones.

Examples of the diseases relating to abnormal gene expression of variouscells include, for example, bone diseases as those relating to bonecells, AIDS as one relating to virus, and cancers as those relating tocancer cells.

Examples of the bone diseases include osteoporosis, hypercalcemia, bonePaget's disease, renal osteodystrophy, rheumatoid arthritis,osteoarthritis, osteogenesis imperfecta tarda, bone damage, periodontalbone disorder, and the like. Examples of AIDS include acquiredimmunodeficiency syndrome caused by human immunodeficiency virus (HIV)infection. Examples of the cancers include gastric cancer, carcinoma ofthe colon and rectum, hepatocellular carcinoma, pancreatic carcinoma,lung cancer, leukemia, malignant lymphoma, carcinoma uteri, ovariancancer, breast cancer, skin cancer and the like.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of hypertension can beconfirmed by administering the compound to various hypertension modelanimals or the like. Examples of hypertension animal models includespontaneous hypertensive rat (SHR), renal hypertensive rat, DOCA-salthypertensive rat and the like (Uehata, M. et al., Nature, 389, 990-994,1997). A compound is orally, intravenously or intraperitoneallyadministered to a hypertension model animal at a dose of 0.1 to 1,000mg/kg, preferably 0.1 to 100 mg/kg, and the diastolic blood pressure ismeasured. The usefulness as a medicament for hypertension can beconfirmed based on an action of reducing the diastolic blood pressure.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of pulmonary hypertension canbe confirmed by using, for example, a rat model of pulmonaryhypertension created by administering monocrotaline to a rat for 2 to 3weeks (Ito, K. M. et al., Am. J. Physiol., 279, H1786-H1795, 2000). Acompound is orally, intravenously or intraperitoneally administered to amodel animal of pulmonary hypertension at a dose of 0.1 to 1,000 mg/kg,preferably 0.1 to 100 mg/kg, and the intrapulmonary pressure ismeasured. The usefulness as a medicament for pulmonary hypertension canbe confirmed based on an action of decreasing the intrapulmonarypressure.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of arteriosclerosis can beconfirmed by using, for example, a rat model of L-NAME-inducedarteriosclerosis (Cir. Res. 89(5):415-21, 2001), a rat model ofballoon-induced neointimal formation (Sawada N. et al., Circulation 101(17):2030-3, 2000) or the like. A compound is orally, intravenously orintraperitoneally administered to a model animal of arteriosclerosis ata dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, andthickening of arteries is observed. The usefulness as a medicament forarteriosclerosis can be confirmed based on an action of suppressingneointimal formation in arteries.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of cerebral circulatorydysfunction can be confirmed by using, for example, a gerbil model ofhippocampal neuronal death (Kirino et al., Brain Res., 239, 57-69, 1982)or the like. A compound is orally, intravenously or intraperitoneallyadministered to the model animal at a dose of 0.1 to 1,000 mg/kg,preferably 0.1 to 100 mg/kg, and the amount of energy-related substancesand survival period of gerbil, or inhibition of late-onset of neuronaldeath is measured. The usefulness as a medicament for cerebralcirculatory dysfunction can be confirmed based on actions formaintaining, improving and activating cerebral metabolic ability, brainand nerve protective action, and action for suppressing formation ofcerebral infarction.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of cardiac diseases can beconfirmed by using, for example, a rat model of myocardial infarctionbased on the ligation of artery (Xia Q. G. et al., Cardiovasc. Res.,49(l):110-7, 2001) or the like. Effectiveness as a medicament forcardiac diseases can be confirmed by orally, intravenouslyor.intraperitoneally administering a compound to the model animal at adose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and observing acardiac tissue fixed by formalin perfusion after ischemic reperfusion.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of disturbances of peripheralcirculation can be confirmed by using, for example, a rat model ofbedsore (Pierce S. M. et al., Am. J. Physiol. Heart Circ. Physiol.,281(l):H67-74, 2001) or the like. Effectiveness as a medicament forbedsore (peripheral circulatory disturbance) can be confirmed by orally,intravenously or intraperitoneally administering a compound to the modelanimal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,compressing the hind leg skin at a pressure of 50 mmHg, and thenobserving a tissue of necrotic area of the lesion or measuringepithelial blood flow of the same.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of disturbances of retinalcirculation can be confirmed by using, for example, rabbit model of rosebengal-mediated argon laser retinal vein photothrombosis (Jpn. J.Ophthalmol., 45(4):359-62, 2001), or the like. Effectiveness as amedicament for retinal circulatory disturbance can be confirmed byorally, intravenously or intraperitoneally administering a compound tothe model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100mg/kg, comparing the degree of retinal circulatory disturbance with thatof a control based on count of laser spots.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of renal failure can beconfirmed by using, for example, a rat model of one-kidney, one-cliprenal hypertension (Kiso to Rinsho, 30, 511-524, 1996). Effectiveness asa medicament for renal failure can be confirmed by orally, intravenouslyor intraperitoneally administering a compound to the model animal at adose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuringthe diuretic effect.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of asthma, for example,bronchial asthma, can be confirmed by using, for example, suppression ofconstriction of an isolated trachea, a model animal of bronchial asthma,inhibition of chemotaxis of human peripheral leucocytes (KunihikoIizuka, Allergy, 47:943, 1998; Kunihiko Iizuka, and Akihiro Yoshii,Jpn.J.Respirol Soc, 37:196, 1999.), or the like. The usefulness as amedicament for bronchial asthma can be confirmed by orally,intravenously or intraperitoneally administering a compound to the modelanimal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, andmeasuring elevation of airway resistance caused by acetylcholineinhalation, or performing histological analysis.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of irritable bowel syndromecan be confirmed by administering the compounds to any of various stressburden model animals. The aforementioned usefulness can be confirmed byadministering a compound to a stress burden model animal, for example, arat model of arresting stress, a CRH-administered rat model (Miyata, K.et al., Am. J. Physiol., 274, G827-831, 1998), or the like. A compoundis orally, intravenously or intraperitoneally administered to a stressburden model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to100 mg/kg, and counting the number of fecal pellets. The usefulness as amedicament for curative medicine of irritable bowel syndrome can beconfirmed based on effect for reducing the number of fecal pellets.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of glaucoma can be confirmedby, for example, measuring intraocular pressure of a rabbit, cat ormonkey after administration of the medicaments by instillation (Surv.Ophthalmol. 41:S9-S18, 1996). The usefulness as a medicament forglaucoma can be confirmed by instilling or orally, intravenously orintraperitoneally administering a compound to a locally anesthetized rator monkey model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1to 100 mg/kg, and measuring the intraocular pressure over time using antonometer.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of dysuria can be confirmed byusing, for example, a model of rhythmic bladder contraction (Kaneko S.et al., Folia Pharmacol. Japon, Vol. 93(2), 55-60, 1989; Nomura N. etal., Folia Pharmacol. Japon, Vol. 94(3), 173-, 1989.) or the like. Theusefulness as a medicament for urinary disturbance can be confirmed byorally, intravenously or intraperitoneally administering a compound toan anesthetized rat or dog at a dose of 0.1 to 1,000 mg/kg, preferably0.1 to 100 mg/kg, and measuring the number of rhythmic contraction offilled bladder (micturition).

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of erectile dysfunction can beconfirmed by a known method, for example, the method described in J.Uro., 151, 797-800, 1994. A compound is dissolved in a hydrophilicointment, 30 mg of the ointment was applied to a rat penis, and the ratis held in an acrylic cylinder for 10 minutes so that the rat was notable to lick the penis. The rat is moved to an acrylic cage of 30 cm×30cm, and videotaped for 60 minutes from the side and the bottom of thecage. Then, the number of erection of the penis per 30 minutes can becounted to confirm the usefulness as a medicament for erectiledysfunction.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forsuppressing cancer metastasis and invasion can be confirmed by, forexample, the method described in Cancer Res., 55:3551-3557 (1995). Theusefulness as a medicament for cancer metastasis and invasion can beconfirmed by orally, intravenously or intraperitoneally administering acompound at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,to a nude mouse transplanted with human cancer cell suspensiontransplantable to immunodeficient mice at the same site (spontaneousmetastasis model), and measuring the metastasized lesion.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of collagen disease can beconfirmed by using, for example, collagen-induced arthritis model of arat or mouse (Griffith, M. M. et al., Arthritis Rheumatism, 24:781,1981; Wooley, P. H. et al., J. Exp. Med., 154:688, 1981). The usefulnessas a medicament for collagen disease can be confirmed by orally,intravenously or intraperitoneally administering a compound to the modelmouse or rat at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100mg/kg, and measuring footpad volume or progression of bone destruction.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of inflammatory bowel diseasecan be confirmed by using a rat model of idiopathic ulcerative colitisinduced by subserosal injection of acetic acid, a model of sodiumdextransulfate-induced colitis, a model of trinitrobenzenesulfonicacid-induced colitis (Kojima et al., Folia. Pharmacol. Jpn., 118,123-130, 2001), or the like. The usefulness as a medicament forinflammatory bowel disease can be confirmed by, for example, orally,intravenously or intraperitoneally administering a compound at a dose of0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, to a rat in whichcolitis is induced by intraintestinal injection of acetic acid,dissecting the rat after several days to two weeks, then observing andmeasuring the ulcer area of the intestinal epithelium, and amount ofleucotriene B4 in a colon homogenate.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of spinal cord injury can beconfirmed by using, for example, a rat model of spinal cord ablation(Sayer F. T. et al., Exp. Neurol., 175(1):282-96, 2002) or the like.Effectiveness as a medicament for spinal cord injury can be confirmed byorally, intravenously or intraperitoneally administering a compound tothe model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100mg/kg, and, after several weeks, examining a tissue of the spinal cordwith a microscope to measure a degree of nerve regeneration.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of pneumonia can be confirmedby using, for example, a mouse model of OVA-induced chronic pneumonia(Henderson W. R. et al., Am. J. Respir. Crit. Care Med., 165(1):108-16,2002) or the like. Effectiveness as a medicament for pneumonia can beconfirmed by orally, intravenously or intraperitoneally administering acompound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably0.1 to 100 mg/kg, and counting number of eosinophils or monocytes in thepulmonary cavity.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of hepatitis can be confirmedby using a mouse model of endotoxin-induced liver injury according to,for example, the method described in J. Immunol., 159, 3961-3967, 1997.The usefulness as a medicament for hepatitis can be confirmed by orally,intravenously or intraperitoneally administering a compound to the mousemodel of endotoxin-induced liver injury at a dose of 0.1 to 1,000 mg/kg,preferably 0.1 to 100 mg/kg, and measuring the plasmic transaminaselevel or amount of hydroxyproline in a hepatic tissue, which areindicators of liver function, or performing histological analysis.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of pancreatitis can beconfirmed by using, for example, a mouse model of cerulein-inductedacute pancreatitis (Niedirau, C. et al., Gastroenterology 88 (5 Pt1):1192-204, 1985) or the like. Effectiveness as a medicament forpancreatitis can be confirmed by orally, intravenously orintraperitoneally administering a compound to the model animal at a doseof 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring theserum amylase activity, or weight of pancreas.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic. and/or therapeutic treatment of nephritis can be confirmedby using, for example, a nephritis rat model prepared by administeringanti-GBM antibodies obtained by immunizing a rabbit with a GBM fractionderived from a rat to a rat (WO01/56988), or the like. A compound isorally, intravenously or intraperitoneally administered to the nephritisrat model at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,and the urinary proteins are measured. The usefulness as a medicamentfor nephritis can be confirmed based on an action of reducing theurinary protein level.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients for suppressingallograft rejection at the time of organ transplantation can beconfirmed by using, for example, a rat model of skin transplantation,rat model of heart transplantation (Ochiai T. et al., Transplant. Proc.,19, 1284-1286, 1987), or the like. Effectiveness as a medicament forsuppressing rejection at the time of organ transplantation can beconfirmed by orally, intravenously or intraperitoneally administering acompound to a model animal at a dose of 0.1 to 1,000 mg/kg, preferably0.1 to 100 mg/kg, and estimating the graft survival ratio.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of rheumatoid arthritis can beconfirmed by using collagen-induced arthritis model of a rat or mouse(Griffith, M. M. et al., Arthritis Rheumatism, 24:781, 1981; Wooley, P.H. et al., J. Exp. Med., 154:688, 1981). The usefulness as a medicamentfor rheumatoid arthritis can be confirmed by orally, intravenously orintraperitoneally administering a compound to a model mouse or model ratat a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, andmeasuring footpad volume or progression of bone destruction.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of chronic obstructivepulmonary disease (COPD) can be confirmed by using, for example,suppression of constriction of an isolated trachea, a model animal ofbronchial asthma, a guinea pig model of tobacco smoke exposition(Fuchigami J. et al., 73rd Meeting of Japanese Pharmacological Society,Collection of Abstracts, 2000), inhibition of chemotaxis of humanperipheral leucocytes or the like. The usefulness as a medicament forCOPD can be confirmed by orally, intravenously or intraperitoneallyadministering a compound to a guinea pig exposed to tobacco smoke at adose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and countingthe number of migrating leucocytes in a bronchoalveolar lavage fluid, orperforming histological analysis.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of hepatic fibrosis can beconfirmed by using a carbon tetrachloride-induced hepatic fibrosis modelaccording to, for example, the method described in J. Hepatol., 35(4),474-81, 2001. The usefulness as a medicament for hepatic fibrosis can beconfirmed by orally, intravenously or intraperitoneally administering acompound to the hepatic fibrosis model at a dose of 0.1 to 1,000 mg/kg,preferably 0.1 to 100 mg/kg, and measuring the plasmic transaminaselevel, or amount of hydroxyproline in a hepatic tissue, which areindicators of liver function, or performing histological analysis.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of pulmonary fibrosis can beconfirmed by using an animal model of Bleomycin-induced pulmonaryfibrosis according to the method described in, for example, Am. J.Respir. Crit. Care Med., 163(1), pp.210-217, 2001. The usefulness as amedicament for pulmonary fibrosis can be confirmed by orally,intravenously or intraperitoneally administering a compound to thepulmonary fibrosis mouse model at a dose of 0.1 to 1,000 mg/kg,preferably 0.1 to 100 mg/kg, and measuring respiratory function, oramount of hydroxyproline in a pulmonary tissue.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of allergy can be confirmed byusing, for example, an atopic dermatitis mouse model or the likeaccording to the method described in, for example, Allergy, 50 (12)1152-1162, 2001. The usefulness as a medicament for allergy can beconfirmed by orally, intravenously or intraperitoneally administering acompound to an NC/Nga mouse pretreated with a surfactant or an organicsolvent at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,when eruption is induced in the mouse by using housedust mite antigens,and measuring the plasmic IgE level, number of eosinophils and the like.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of thrombosis can be confirmedby using, for example, a rabbit model of experimentally-induced venousthrombus (Maekawa, T. et al., Trombos. Diathes. Haemorrh., 60,pp.363-370, 1974), or the like. Effectiveness as a medicament forthrombosis can be confirmed by orally, intravenously orintraperitoneally administering a compound to the model animal at a doseof 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and estimating theincidence of thrombus.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of bone disease can beconfirmed by using, for example, a mouse model of osteoporosis preparedby ovariectomy (OVX mouse, Golub, L. M. et al., Ann. N.Y. Acad. Sci.,878, pp.290-310, 1999). A compound is orally, intravenously orintraperitoneally administered to the OVX mouse at a dose of 0.1 to1,000 mg/kg, preferably 0.1 to 100 mg/kg, and deciduous dental roots aremeasured, or weight of skeletal bones is measured. The usefulness as amedicament for bone disease can be confirmed based on an action forsuppressing periodontal breakdowns, or an action for suppressingskeletal bone weight loss.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of AIDS can be confirmed byusing, for example, a rhesus monkey model of SIV-infection (Crub S. etal., Acta Neuropathol., 101(2), pp.85-91, 2001) or the like.Effectiveness as a medicament for AIDS can be confirmed by orally,intravenously or intraperitoneally administering a compound to the modelanimal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, andquantifying the SIV mRNA level in blood.

Usefulness of the compounds of the present invention represented by theaforementioned formula (1) as active ingredients of medicaments forprophylactic and/or therapeutic treatment of cancer can be confirmed byusing, for example, a mouse model of ultraviolet ray irradiation-inducedskin cancer, a nude mouse model of tumor xenograft (Orengo I. F. et al.,Arch Dermatol., 138(6), pp.823-4, 2002; Ki D. W. et al., AnticancerRes., 22(2A), pp.777-88, 2002) or the like. Effectiveness as amedicament for cancer can be confirmed by orally, intravenously orintraperitoneally administering a compound to a model animal at a doseof 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and observingprogression or reduction of the grafted cancer tissues on the bodysurface.

Further, when test compounds of the compounds of the present inventionor salts thereof were introduced into wells of a 96-well plate at aconcentration three times higher than the IC₅₀ values obtained in TestExample 1, and the cell suspension prepared in Test Example 1 was addedat a density of 10⁶/well, incubated for 30 minutes at room temperatureand stained with trypan blue to determine the survival rates of thecells, a viability as high as 90% or more was observed in all the wells.Furthermore, when the compounds of the present invention or saltsthereof were orally administered to mice every day at a dose of 30 mg/kgfor 5 days, death was not observed. Therefore, the compounds of thepresent invention had no particular problem also in safety.

As the active ingredients of the medicaments of the present invention,the compounds represented by the aforementioned formula (1), andphysiologically acceptable salts thereof can be used. The aforementionedsubstance, per se, may be administrated as the medicament of the presentinvention. A pharmaceutical composition containing one or more kinds ofthe aforementioned substances as the active ingredients and one or morekinds of pharmaceutical additives can be generally prepared andadministrated orally or parenterally (e.g., intravenous administration,intramuscular administration, subcutaneous administration, transdermaladministration, intrapulmonary administration, intranasaladministration, instillation, intraurethral administration, intravaginaladministration, sublingual administration, intrarectal administration,and the like) to human or an animal other than human. The aforementionedpharmaceutical composition can be prepared in a dosage form suitable foran intended administration route. More specifically, examples of thepharmaceutical composition suitable for oral administration include oraldrug products (tablets, film-coated tablets, intraoral collapsingtablets, hard capsules, soft capsules, powders, fine granules, granules,dry syrups, syrups, pills, troches and the like), and examples of thepharmaceutical composition suitable for parenteral administrationinclude injections (liquid dosage forms, lyophilized dosage forms,suspensions and the like), inhalants, suppositories, transdermallyabsorbed agents (e.g., tapes), ointments, ophthalmic solutions,ophthalmic ointments, ophthalmic membrane adherent agents and the like.For glaucoma, preferred examples of the dosage form include oral drugproducts, ophthalmic solutions, ophthalmic ointments, and ophthalmicmembrane adherent agents. Further, preferred dosage forms for bronchialasthma or chronic obstructive pulmonary disease include oral drugproducts, inhalants (for example, a method of inhaling powder of thepharmaceutical composition or a liquid dosage form prepared bydissolving or suspending the pharmaceutical composition in a solvent asit is, or inhaling mist thereof by using a sprayer called atomizer ornebulizer), and transdermal preparations.

These pharmaceutical compositions can be prepared in a conventionalmanner by using pharmaceutical additives usually used in this field(e.g., excipients, disintegrants, binders, lubricants, colorants,buffering agents, coating agents, flavors, fragrances, emulsifyingagents, isotonic agents, solubilizing agents, preservatives, viscosityimprovers, pH adjusters and the like). Examples of the excipientsinclude saccharides such as lactose, sucrose, and trehalose, sugaralcohols such as D-mannitol, erythritol, xylitol, and sorbitol, starchessuch as maize starch, crystalline cellulose, calcium phosphate and thelike, examples of the disintegrants include starches, partiallypregelatinized starch, carmellose and metal salts thereof,croscarmellose sodium, sodium carboxymethyl starch, agar powder,crospovidone, low substituted hydroxypropylcellulose and the like,examples of the binders include hydroxypropylmethylcellulose,hydroxypropylcellulose, polyvinyl alcohol, methylcellulose,ethylcellulose, popidone, acacia powder, pullulan, pregelatinized starchand the like, and examples of the lubricants include stearic acid andmetal salts thereof, talc, silicic acid and metal salts thereof,salt-hardened oil, sucrose fatty acid esters, sodium laurylsulfate,sodium stearyl fumarate and the like

When solid pharmaceutical compositions are prepared, there are usedpharmaceutical additives including, for example, sucrose, lactose,glucose, fructose, trehalose, D-mannitol, sorbitol, erythritol, xylitol,maltitol, maize starch, potato starch, wheat starch, rice starch,crystalline cellulose, carmellose, carmellose calcium, low substitutedhydroxypropylcellulose, croscarmellose sodium, crospovidone, dextrin,cyclodextrin, dextran, agar, xanthane gum, guar gum, rosin, acacia,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, polyvinyl alcohol, povidone, pregelatinized starch,partly pregelatinized starch, pullulan, pectin, polysorbate,polyethylene glycol, propylene glycol, glycerol, magnesium stearate,talc, light anhydrous silicic acid, hydrated silicon dioxide, kaolin,sucrose fatty acid esters, sodium laurylsulfate, silicic acid, aluminumsilicate, magnesium aluminometasilicate, calcium carbonate, sodiumhydrogencarbonate, sodium chloride, sodium citrate, citric acid,succinic acid, tartaric acid, hydrogenated castor oil, hydrogenatedtallow, stearic acid, cetanol, olive oil, orange oil, soybean oil, cacaobutter, carnauba wax, paraffin, vaseline, triacetin, triethyl citrate,iron oxide, caramel, tartrazine, vanillin, carmellose sodium, cellulosederivatives such as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, carboxyvinyl polymer, cellulose acetatephthalate, cellulose acetate trimellitate, ethylcellulose, and celluloseacetate, polyethylene glycol, gelatin, shellac, methacrylic acid andderivatives thereof as well as copolymers thereof, ethylcelluloseaqueous dispersion (Aquacoat), silicone oil, triacetin and the like. Thetablets can be tablets having usual surfaces of the tablets as required,and examples include sugar-coated tablets, enteric coating tablets,film-coated tablets, bilayer tablets, and multilayer tablets.

When semi-solid pharmaceutical compositions are prepared, there are usedpharmaceutical additives including, for example, animal fats and oils(olive oil, maize oil, castor oil and the like), mineral fats and oils(vaseline, white petrolatum, solid paraffin and the like), waxes (ojobaoil, carnauba wax, beeswax and the like), partially or totallysynthesized glycerol fatty acid esters. Examples of commercial productsinclude Witepsol (Dynamit Nobel), Pharmasol (Nippon Oil & Fats) and thelike. When liquid pharmaceutical compositions are prepared,pharmaceutical additives including, for example, sodium chloride,glucose, sorbitol, glycerol, olive oil, propylene glycol, ethyl alcoholand the like can be used. When injections are prepared, sterile liquidmedia, for example, physiological saline, isotonic solutions, oilyliquids such as sesame oil and soybean oil are used. Further, ifnecessary, suitable suspending agents such as carboxymethylcellulosesodium, nonionic surfactants, solubilizing agents such as benzylbenzoate and benzyl alcohol and the like may be used together. When eyedrops are prepared, they can be prepared as aqueous liquids or aqueoussolutions. For example, aqueous solutions can be prepared by using asterile aqueous solution for injections. To these liquids forinstillation, various additives such as buffers (borate buffers, acetatebuffers, carbonate buffers and the like are preferred in view ofreduction of stimulus), isotonic agents (for example, sodium chloride,potassium chloride and the like can be mentioned), preservatives (forexample, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzyl alcohol,chlorobutanol and the like can be mentioned), viscosity improvers (forexample, methylcellulose, sodium carboxymethylcellulose and the like canbe mentioned) and the like may be optionally added. As for preparationof inhalants, when the composition is inhaled as powder, for example,preparation of the aforementioned solid pharmaceutical composition canbe referred to, and the obtained powder is preferably furtherpulverized. Further, when the composition is inhaled as a liquid,preferable methods include a method of preparing the pharmaceuticalcomposition by referring to the aforementioned preparation of solidpharmaceutical composition to prepare a solid composition and dissolvingthe solid in distilled water or a suitable solvent to obtain amedicament solution upon use, or a method of preparing thepharmaceutical composition by referring to the aforementionedpreparation of liquid pharmaceutical composition to obtain a medicamentsolution. The size of particles in the aforementioned powder ormedicament solution is preferably a particle size suitable forinhalation, and the upper limit of the size is, for example, preferably100 μm or less, more preferably 50 μm or less, particularly preferably10 μm or less. The lower limit of the particle size is not particularlylimited, and a smaller particle size is more preferred.

A content of the active ingredient in the aforementioned pharmaceuticalcomposition can be suitably chosen depending on a dosage form. Thecontent may be, for example, about 0.1 to 100% by weight, preferablyabout 1 to 50% by weight, based on the total weight of the composition.A dose of the medicament of the present invention can be suitablydetermined for each administration in consideration of the age, weight,sexuality of a patient, the type of a disease, the severity ofpathological condition and the like. Examples of the doses include, forexample, about 1 to 500 mg, preferably about 1 to 100 mg, and mostpreferably about 1 to 30 mg. These doses can be administered once in aday or several times a day as divided portions.

The compounds represented by the aforementioned formula (1) orphysiologically acceptable salts thereof may be used optionally incombination with other one or more kinds of medicaments (a medicamentused in combination with the compounds represented by the aforementionedformula (1) or physiologically acceptable salts thereof is hereinafterreferred to as a “medicament for combinational use”). For that purpose,administration time of each of the compound represented by theaforementioned general formula (1) or a physiologically acceptable saltand a medicament for combinational use is not limited, and they may besimultaneously administered, or administered with an interval.Therefore, the compound represented by the aforementioned formula (1) ora physiologically acceptable salt thereof and the medicament forcombinational use may be prepared in separate forms, or they may bemixed and formed in a single form. When they are mixed, mixing ratio ofthe compound represented by the aforementioned formula (1) or aphysiologically acceptable salt thereof and the medicament forcombinational use, form of the both after mixing and the like may besuitably determined depending on an object to be administered, a routeof administration, a disease to be treated, symptoms, physicochemicalproperties, ease of administration and the like.

The dose of the medicament for combinational use can be suitably chosenon the basis of a clinically used dosage. The medicament forcombinational use may be a low molecular weight compound, peptide,polymer such as protein, polypeptide, nucleic acid oligomer, peptidenucleic acid (PNA) oligomer, and antibody, vaccine or the like. Forexample, when the object of administration is a human, the medicamentfor combinational use may be used in an amount chosen from the range offrom 0.01 to 100 weight parts relative to 1 weight part of the compoundrepresented by the aforementioned formula (1) or a physiologicallyacceptable salt thereof, and the medicament can be used in a preferredform, for example, in the form of an oral preparation, injection (liquiddosage form, suspension and the like), drip infusion, inhalant,suppository, transdermally absorbed agent (e.g., tape), ointment,ophthalmic solution, ophthalmic ointment, ophthalmic membrane adherentagent or the like using the aforementioned pharmaceutical additives asrequired.

The aforementioned medicament for combinational use can be optionallychosen from various medicaments of which diseases to be applied arethose relating to contraction of various cells, those relating tomorphological change of various cells, those relating to migration ofvarious cells, those relating to release of various cells, thoserelating to aggregation of various cells, those relating to apoptosis ofvarious cells, and/or those relating to abnormal gene expression ofvarious cells and the like, depending on object of administration,administration route, objective disease, symptoms and the like

For example, for glaucoma, which is exemplified in this specification asa disease relating to contraction of various cells, the medicament forcombinational use can be optionally chosen from non-selectiveβ-adrenergic receptor antagonists (e.g., timolol maleate and the like),selective β-adrenergic receptor antagonists (e.g., betaxolol and thelike), cholinergic receptor agonists (e.g., pilocarpine hydrochlorideand the like), choline esterase inhibitors (e.g., fisostigmine and thelike), carbonic anhydrase inhibitors (e.g., brinzolamide and the like),prostaglandine derivatives (e.g., latanoprost and the like),non-selective sympatholytic agents (e.g., epinephrine hydrochloride andthe like), selective α1 adrenergic receptor antagonists (e.g., bunazosinhydrochloride and the like), selective α2 adrenergic receptorantagonists (e.g., brimonidin tartrate and the like), α1- andβ-adrenergic receptor antagonists (e.g., nipradilol and the like),α-adrenergic receptor agonists (e.g., dipivefrin hydrochloride and thelike), calcium antagonists (e.g., iganidipin and the like), and so forth(AI Report, Cima Science Journal, 2002).

For example, for bronchial asthma, which is exemplified in thisspecification as a disease relating to contraction of various cells oras a disease relating to migration of various cells, the medicament forcombinational use can be optionally chosen from suppressants of chemicalmediator release (e.g., sodium cromoglicate and the like), anti-histamicagents (e.g., epinastine hydrochloride and the like), suppressants oflipid mediator production, suppressants of Th2 cytokine production(e.g., suplatast tosilate and the like), bronchodilators, steroid agentsand the like. Examples of the suppressants of chemical mediator releaseinclude thromboxane A2 receptor antagonists (e.g., seratrodast and thelike), leukotriene receptor antagonists (e.g., pranlukast and the like),and the like. Examples of the bronchodilators include anticholinergicagents (e.g., ipratropium bromide and the like), xantine derivatives(e.g., theophylline and the like), β2-adrenergic receptor antagonists(e.g., formoterol and the like) and the like. Examples of the steroidagents include oral steroids (e.g., predonizolone and the like),inhalant steroids (e.g., fluticasone propionate and the like) and thelike (AI Report, Cima Science Journal, 2002).

For example, for chronic obstructive pulmonary disease (COPD), which isexemplified in this specification as a disease relating to contractionof various cells or as a disease relating to migration of various cells,the medicament for combinational use can be optionally chosen frombronchodilators, steroid agents and the like. Anticholinergic agents andsteroid agents that can be exemplified as the bronchodilators are thesame as those explained above (AI Report, Cima Science Journal, 2002).

Those mentioned above are examples for selection of the medicament forcombinational use, and the medicament for combinational use is notlimited to the examples mentioned above.

EXAMPLES

The present invention will be further specifically explained withreference to examples. However, the scope of the present invention isnot limited to the following examples.

For thin layer chromatography (TLC), Precoated Silica Gel 60 F254(produced by Merck) was used. After development with chloroform:methanol(100:1 to 4:1), or ethyl acetate:n-hexane (100:1 to 1:10), spots wereobserved by UV irradiation (254 nm) or coloration with ninhydrine orphosphomolybdic acid. For drying organic solvent, anhydrous magnesiumsulfate or anhydrous sodium sulfate was used. For flash columnchromatography, Silica gel 60N (spherical shape, neutral, 40 to 100 μm,produced by Kanto Chemicals) was used. For preparative thin layerchromatography (PTLC), Precoated Silica Gel 60 F254 (20×20 cm,thickness: 2 mm, produced by Merck) was used. Elution was performed withhexane:ethyl acetate=1:0 to 0:1, or chloroform:ethanol=10:1 to 1:1. Forthe measurement of nuclear magnetic resonance (NMR) spectra, themeasurement was performed by using Gemini-300 (FT-NMR, produced byVarian), or AL-300 (FT-NMR, produced by JOEL). As a solvent, deuteratedchloroform was used, unless otherwise indicated. Chemical shifts weremeasured by using tetramethylsilane (TMS) as an internal standard, andindicated with δ (ppm), and binding constant was indicated with J (Hz).Mass spectrum (MS) was measured by liquid chromatography-massspectrometry (LC-MS). Platform-LC type mass spectrometry apparatus(produced by Micromass) was used as the mass spectrometer, and themeasurement was performed by the electrospray ionization (ESI) method.As the liquid chromatography apparatus, an apparatus produced by GILSONwas used. As the separation column, Mightysil RP-18 GP 50-4.6 (producedby Kanto Chemicals) was used. Elution was generally performed at a flowrate of 2 ml/minute using a linear gradient of 5 to 100% (v/v) SolutionB [acetonitrile containing 0.1% (v/v) acetic acid] in Solution A [watercontaining 0.1% (v/v) acetic acid] from 0 minute to 5 minutes as thesolvent.

Example 1

N-[(5-Isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-35)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-1,3-propylenediamine(Intermediate 1)

A solution of N-(tert-butoxycarbonyl)-1,3-propylenediamine (2.09 g,Tokyo Kasei Kogyo) and triethylamine (3.4 ml, Tokyo Kasei Kogyo) indichloromethane (20 ml) was added with a solution ofisoquinoline-5-sulfonyl chloride (2.73 g, prepared according to JapanesePatent Unexamined Publication (Kokai) No. 61-227581) in dichloromethane(15 ml) with stirring and ice cooling and stirred at room temperaturefor 14 hours and 30 minutes. The reaction mixture was washedsuccessively with saturated aqueous sodium hydrogencarbonate andsaturated brine. The organic layer was dried, and then the solvent wasevaporated under reduced pressure. Then, the residue was purified byflash column chromatography (chloroform:methanol=50:1) to obtain thetitle compound (4 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-(3-phenylpropyl)-1,3-propylenediamine(Intermediate 2)

A solution of Intermediate 1 (640 mg),1,1′-azobis(N,N-dimethylformamide) (1200 mg, Aldrich or preparedaccording to Chemistry Letters, 539 (1994)) and 3-phenyl-1-propanol (710μl, Tokyo Kasei Kogyo) in tetrahydrofuran (30 ml) was added withtri(n-butyl)phosphine (1.75 ml, Tokyo Kasei Kogyo) with stirring and icecooling and stirred at room temperature under argon atmosphere for 13.5hours. The precipitates in the reaction mixture were removed byfiltration, and then the solvent was evaporated from the filtrate underreduced pressure. The residue was purified by flash columnchromatography (hexane/ethyl acetate mixed solvent) to obtain the titlecompound (913 mg, mixture with a small amount of 3-phenyl-1-propanol).

(Step C) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride

Intermediate 2 (913 mg) was added with 10% hydrogen chloride/methanolsolution (18 ml, Tokyo Kasei Kogyo) at room temperature and stirred for25 minutes under reflux by heating. After the reaction, the solvent wasevaporated under reduced pressure, and the residue was crystallized froma mixed solvent of methanol and diethyl ether to obtain the titlecompound (653 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.65-1.90 (4H, m), 2.39-2.45 (2H, m),2.67-2.84 (2H, m), 3.21-3.34 (2H, m), 3.35-3.46 (2H, m), 7.05 (1H, d,J=6.9 Hz), 7.11-7.29 (4H, m), 7.85-8.05 (4H, m), 8.42 (1H, d, J=7.4 Hz),8.50 (1H, d, J=6.3 Hz), 8.60 (1H, d, J=8.5 Hz), 8.75 (1H, d, J=6.3 Hz),9.71 (1H, s)

MS (m/z): 384 (MH+)

Example 2

N-[(5-Isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-37)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[2-(2-thienyl)ethyl]-1,3-propylenediamine(Intermediate 3)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (333 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), 2-(2-thienyl)ethanol (385 mg, Aldrich)and 1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 3 (238 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (202 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.82-1.96 (2H, m), 2.70-2.83 (2H, m),2.94-3.04 (2H, m), 3.41-3.55 (4H, m), 6.70-6.80 (2H, m), 7.13-7.20 (1H,m), 7.96-8.27 (4H, m), 8.47-8.77 (4H, m), 9.76-9.86 (1H, br.s)

MS (m/z): 376 (MH+)

Example 3

4-{N-[(5-Isoquinolyl)sulfonyl]-N-(3-phenylpropyl)}aminopiperidinehydrochloride (Exemplary Compound No. 3-205)

(Step A) Synthesis of1-(tert-butoxycarbonyl)-4-N-[(5-isoquinolyl)sulfonyl]-aminopiperidine(Intermediate 4)

According to the method of Example 1, Step B, the title compound (665mg) was obtained from (5-isoquinolyl)sulfonyl chloride (455 mg),4-amino-1-(tert-butoxycarbonyl)piperidine (441 mg, Asta Tech) andtriethylamine (335 μl).

(Step B) Synthesis of1-(tert-butoxycarbonyl)-4-{N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)}aminopiperidine(Intermediate 5)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (357 mg) was obtained from Intermediate 4 (392 mg),tri(n-butyl)phosphine (747 μl), 3-phenyl-1-propanol (405 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step C) Synthesis of4-{N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)}-aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 5 (254 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (192 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.64-1.83 (4H, m), 1.98-2.15 (2H, m),2.88-3.03 (2H, m), 3.20-3.30 (4H, m), 3.90-4.20 (3H, m), 7.08-7.30 (5H,m), 7.91-8.00 (1H, m) 8.42-9.13 (6H, m), 9.71-9.82 (1H, br.s)

MS (m/z): 410 (MH+)

Example 4

N-[(5-Isoquinolyl)sulfonyl]-N-(4-phenylbutyl)-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-47)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-(4-phenylbutyl)-1,3-propylenediamine(Intermediate 6)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (348 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), 4-phenyl-1-butanol (462 μl, Tokyo KaseiKogyo) and 1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-(4-phenylbutyl)-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 6 (249 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (188 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.28-1.48 (4H, m), 1.77-1.87 (2H, m),2.40-2.46 (2H, m), 2.67-2.78 (2H, m), 3.25-3.31 (2H, m), 3.36-3.41 (2H,m), 7.01-7.05 (2H, m), 7.13-7.27 (3H, m), 7.94-8.12 (4H, m), 8.47-8.65(3H, m), 8.76 (1H, dd, J=3, 6.6 Hz), 9.72-9.70 (1H, br.s)

MS (m/z): 398 (MH+)

Example 5

N-[(4-Methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-715)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(4-bromo-5-isoquinolyl)-sulfonyl]-1,3-propylenediamine(Intermediate 7)

According to the method of Example 1, Step A, a solution ofN-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) andtriethylamine (335 μl) in dichloromethane (3 ml) was added with asolution of (4-bromo-5-isoquinolyl)sulfonyl chloride (483 mg, preparedfrom 4-bromo-5-aminoisoquinoline obtained in Reference Example 1according to the method described in Japanese Patent No. 2763791) indichloromethane (3 ml) with stirring and ice cooling and stirred at roomtemperature for 20 hours. The reaction mixture was successively washedwith saturated aqueous sodium hydrogencarbonate twice and with saturatedbrine, and the organic layer was dried over anhydrous sodium sulfate(Wako Pure Chemical Industries). Then, the solvent was evaporated underreduced pressure to obtain a residue (711 mg). Subsequently, accordingto the method of Example 1, Step B with the modifications that thereaction was carried out for 24 hours, and the compound was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1), the titlecompound (540 mg) was obtained from the aforementioned residue,tri(n-butyl)phosphine (747 μl), 3-phenyl-1-propanol (405 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(4-methyl-5-isoquinolyl)-sulfonyl]-N′-(3-phenylpropyl)-1,3-propylenediamine(Intermediate 8)

Under nitrogen atmosphere, a suspension of Intermediate 7 (540 mg) anddichloro(1,3-bis(diphenylphosphino)propane)nickel(II) (5.2 mg, TokyoKasei Kogyo) in tetrahydrofuran (5 ml) was added dropwise with asolution of methyl iodide magnesium in diethyl ether (0.84 M, 1.3 ml,Kanto Chemicals) and stirred with heating at 50° C. for 15 hours. Thereaction mixture was returned to room temperature and slowly added withwater (2.5 ml) and then 2 N aqueous sodium hydroxide (10 ml). Theinsoluble matters were removed by filtration, and then the targetcompound was extracted three times with ethyl acetate (30 ml for eachtime). The combined organic layer was washed once with saturated brine(30 ml) and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtainthe title compound (143 mg).

(Step C) Synthesis ofN-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(5° C., 2 hours) by using Intermediate 8 (87 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and the solvent was evaporated under reduced pressure.The residue was added with methanol (1 ml) and diethyl ether (3 ml). Thedeposited precipitates were collected by filtration and washed withdiethyl ether to obtain the title compound (70 mg) as white powderysolid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.97-2.08 (4H, m), 2.58-2.63 (2H, m),2.79-2.87 (2H, m), 3.03 (3H, d, J=2.1 Hz), 3.44-3.57 (4H, m), 7.16-7.30(5H, m), 7.90-8.19 (5H, m), 8.58-8.68 (2H, m), 9.58-9.65 (1H, br.s)

MS (m/z): 398 (MH+)

Example 6

N-[(5-Isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-46)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine(Intermediate 9)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (346 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), 2-(phenylsulfonyl)ethanol (359 μl,Aldrich) and 1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 9 (266 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (203 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.83 (2H, m), 2.70-2.81 (2H, m),3.33-3.69 (6H, m), 7.66-8.00 (9H, m), 8.23-8.32 (2H, m), 8.55-8.75 (2H,m), 9.71 (1H, s)

MS (m/z): 434 (MH+)

Example 7

N-[(5-Isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediaminehydrochloride (Exemplary Compound No. 3-12)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-ethylenediamine(Intermediate 10)

According to the method of Example 1, Step A, the title compound (246mg) was obtained from (5-isoquinolyl)sulfonyl chloride (455 mg),N-(2-aminoethyl)carbamic acid tert-butyl ester (353 mg, Tokyo KaseiKogyo) and triethylamine (335 μl).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[2-(phenylsulfonyl)ethyl]ethylenediamine(Intermediate 11)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (337 mg) was obtained from Intermediate 10 (352 mg),tri(n-butyl)phosphine (747 μl), 2-(phenylsulfonyl)ethanol (359 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step C) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-ethylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 11 (260 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (197 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.85-2.96 (2H, m), 3.51-3.61 (4H, m),3.72-3.78 (2H, m), 7.66-7.71 (2H, m), 7.78-7.83 (1H, m), 7.87-7.90 (2H,m), 7.95-8.01 (1H, m), 8.17 (3H, br.s), 8.40-8.43 (1H, m), 8.50-8.54(1H, m), 8.68 (1H, d, J=8.1 Hz), 8.77 (1H, d, J=6.6 Hz), 9.79 (1H, s)

MS (m/z): 420 (MH+)

Example 8

N-[(1-Amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-647)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(1-chloro-5-isoquinolyl)-sulfonyl]-1,3-propylenediamine(Intermediate 12)

According to the method of Example 1, Step A, a solution ofN-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) andtriethylamine (335 μl) in dichloromethane (3 ml) was added with asolution of (1-chloro-5-isoquinolyl)sulfonyl chloride (524 mg, preparedfrom (1-chloro-5-isoquinolyl)sulfonyl chloride hydrochloride accordingto the method of Japanese Patent Unexamined Publication (Kokai) No.63-2980) in dichloromethane (3 ml) with stirring and ice cooling andstirred at room temperature for 20 hours. The reaction mixture wassuccessively washed with saturated aqueous sodium hydrogencarbonatetwice and with saturated brine. The organic layer was dried overanhydrous sodium sulfate (Wako Pure Chemical Industries), and then thesolvent was evaporated under reduced pressure. Then, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1).to obtain the title compound (640 mg).

(Step B) Synthesis ofN-[(i-amino-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-1,3-propylenediamine(Intermediate 13)

A solution of Intermediate 12 (400 mg) in 1,4-dioxane (2 ml, Wako PureChemical Industries) was added with 28% aqueous ammonia (2 ml, Wako PureChemical Industries) and stirred in a sealed tube with heating at 130°C. for 24 hours. The reaction mixture was cooled to room temperature,then added with saturated aqueous sodium hydrogencarbonate and extractedthree times with dichloromethane (30 ml for each time). The combinedorganic layer was dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The obtained light yellowsolid was recrystallized from methanol to obtain the title compound (228mg) as white powdery solid.

(Step C) Synthesis ofN-[(1-amino-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-N-(3-phenylpropyl)-1,3-propylenediamine(Intermediate 14)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (ethyl acetate:methanol=30:1), thetitle compound (150 mg) was obtained from Intermediate 13 (190 mg),tri(n-butyl)phosphine (374 μl), 3-phenyl-1-propanol (203 μl) and1,1′-azobis(N,N-dimethylformamide) (259 mg).

(Step D) Synthesis ofN-[(1-amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(5° C., 2 hours) by using Intermediate 14 (125 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (90 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.67-1.86 (4H, m), 2.39-2.49 (2H, m),2.65-2.74 (2H, m), 3.15-3.70 (4H, m), 7.04-7.28 (5H, m), 7.61 (1H, d,J=7.5 Hz), 7.80-7.91 (2H, m), 8.05 (3H, br.s), 8.38 (1H, d, J=7.5 Hz),8.95 (1H, d, J=8.1 Hz), 9.52 (1.5H, br.s), 13.90 (0.5H, br.s)

MS (m/z): 399 (MH+)

Example 9

N-[(1-Amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediaminehydrochloride (Exemplary Compound No. 3-624)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(1-chloro-5-isoquinolyl)-sulfonyl]ethylenediamine(Intermediate 15)

According to the method of Example 1, Step A, the title compound (617mg) was obtained from (1-chloro-5-isoquinolyl)sulfonyl chloride (524mg), N-(2-aminoethyl)carbamic acid tert-butyl ester (353 mg) andtriethylamine (335 μl).

(Step B) Synthesis ofN-[(1-amino-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-ethylenediamine(Intermediate 16)

According to the method of Example 8, Step B, the title compound (220mg) was obtained from Intermediate 15 (386 mg) as white powdery solid.

(Step C) Synthesis ofN-[(1-amino-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-N-[2-(phenylsulfonyl)ethyl]ethylenediamine(Intermediate 17)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (ethyl acetate:methanol=20:1), thetitle compound (134 mg) was obtained from Intermediate 16 (183 mg),tri(n-butyl)phosphine (374 μl), 2-(phenylsulfonyl)ethanol (180 μl) and1,1′-azobis(N,N-dimethylformamide) (259 mg).

(Step D) Synthesis ofN-[(l-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)-ethyl]ethylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 17 (134 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature and then added with diethyl ether (2.5 ml). Thedeposited precipitates were collected by filtration and washed withdiethyl ether to obtain the title compound (100 mg) as white powderysolid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.90-3.00 (2H, m), 3.49-3.59 (4H, m),3.72-3.78 (2H, m), 7.56 (1H, d, J=7.2 Hz), 7.66-7.72 (2H, m), 7.78-7.92(5H, m), 8.15 (3H, br.s), 8.33 (1H, d, J=6.9 Hz), 8.98 (1H, d, J=8.1Hz), 9.55 (1.5H, br.s), 13.90 (0.5H, br.s)

MS (m/z): 435 (MH+)

Example 10

3-[(1-Amino-5-isoquinolyl)oxy]propylamine hydrochloride (ExemplaryCompound No. 1-9)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-3-[(1-chloro-5-isoquinolyl)oxy]-propylamine(Intermediate 18)

A suspension of 1-chloro-5-hydroxyisoquinoline (539 mg, synthesizedaccording to the method described in a reference (Georgian, V. et al.,J. Org. Chem., 27, 4571 (1962))), (3-hydroxypropyl)carbamic acidtert-butyl ester (1.58 g, Tokyo Kasei Kogyo) and1,1′-azobis(N,N-dimethylformamide) (1.55 g) in tetrahydrofuran (8 ml)was added with tri(n-butyl)phosphine (2.24 ml) with ice cooling andstirred at room temperature for 24 hours. The deposited solid wasremoved by filtration, and the solvent was evaporated under reducedpressure. Then, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound(860 mg) as white powdery solid.

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-3-[1-(4-methoxybenzyl)amino-5-isoquinolyl]oxy]propylamine(Intermediate 19)

The title compound was synthesized from Intermediate 18 according to themethod described in a reference (Buchwald, S. L., J. Org. Chem., 65,1158 (2000)). That is, a suspension of Intermediate 18 (674 mg), tris(dibenzylideneacetone)dipalladium(0) (92 mg, Aldrich),2-(di-tert-butylphosphino)biphenyl (119 mg, Strem Chemicals),4-methoxybenzylamine (329 mg, Tokyo Kasei Kogyo) and sodiumtert-butoxide (269 mg, Tokyo Kasei Kogyo) in toluene (5 ml) was stirredwith heating at 80° C. under nitrogen atmosphere for 2 hours. Thereaction mixture was cooled to room temperature and added with ethylacetate (5 ml). The insoluble matters were removed by filtration throughCelite. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (525 mg).

(Step C) Synthesis ofN-(tert-butoxycarbonyl)-3-[(1-amino-5-isoquinolyl)oxy]-propylamine(Intermediate 20)

Intermediate 19 (438 mg) was dissolved in 95% trifluoroacetic acid (5ml) and stirred with heating at 50° C. for 20 hours. The reactionmixture was returned to room temperature, and the solvent was evaporatedunder reduced pressure. The residue was dissolved in methanol (5 ml),added with triethylamine (558 μl) and di-tert-butyl dicarbonate (437 mg,Wako Pure Chemical Industries) and stirred at room temperature for 2hours. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:3) to obtain the title compound (222 mg).

(Step D) Synthesis of 3-[(1-amino-5-isoquinolyl)oxy]propylaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 20 (159 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (116 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.91-2.22 (2H, m), 3.00-3.06 (2H, m), 4.29(2H, t, J=5.9 Hz), 7.37 (1H, dd, J=2.4, 7.2 Hz), 7.48 (1H, d, J=8.1 Hz),7.68-7.74 (2H, m), 8.10-8.30 (4H, m), 9.22 (1.4H, br.s), 13.70 (0.6H,br.s)

MS (m/z): 218 (MH+)

Example 11

3-[(1 -Amino-5-isoquinolyl)oxy]methylpiperidine hydrochloride (ExemplaryCompound No. 1-11)

(Step A) Synthesis of1-(tert-butoxycarbonyl)-3-[(1-chloro-5-isoquinolyl)oxy]-methylpiperidine(Intermediate 21)

According to the method of Example 10, Step A, the title compound (960mg) was obtained from 1-chloro-5-hydroxyisoquinoline (539 mg),(3-hydroxymethylpiperidine)carbamic acid tert-butyl ester (1.94 g,Murphy, Larry), tri(n-butyl)phosphine (2.24 ml) and1,1′-azobis(N,N-dimethylformamide) (1.55 g).

(Step B) Synthesis of1-(tert-butoxycarbonyl)-3-[1-(4-methoxybenzyl)amino-5-isoquinolyl)oxy]methylpiperidine(Intermediate 22)

According to the method of Example 10, Step B, the title compound (573mg) was obtained from Intermediate 21 (754 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), 4-methoxybenzylamine (329mg) and sodium tert-butoxide (269 mg).

(Step C) Synthesis of1-(tert-butoxycarbonyl)-3-[(1-amino-5-isoquinolyl)oxy]-methylpiperidine(Intermediate 23)

According to the method of Example 10, Step C, the title compound (250mg) was obtained from Intermediate 22 (478 mg), 95% trifluoroacetic acid(5 ml), triethylamine (558 μl) and di-tert-butyl dicarbonate (437 mg).

(Step D) Synthesis of 3-[(1-amino-5-isoquinolyl)oxy]methylpiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 23 (179 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (132 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.42-1.55 (1H, m), 1.73-1.93 (3H, m),2.30-2.43 (1H, m), 2.80-2.92 (2H, m), 3.21-3.44 (4H, m), 4.07-4.20 (2H,m), 7.38 (1H, dd, J=1.8, 6.9 Hz), 7.48 (1H, d, J=8.1 Hz), 7.68-7.74 (2H,m), 8.17 (1H, d, J=8.1 Hz), 9.10-9.50 (3.4H, m), 13.68 (0.6H, br.s)

MS (m/z): 258 (MH+)

Example 12

N-[(1-Hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediaminehydrochloride (Exemplary Compound No. 3-318)

(Step A) Synthesis ofN-[(1-chloro-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-N-[2-(phenylsulfonyl)ethyl]ethylenediamine(Intermediate 24)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1), thetitle compound (416 mg) was obtained from Intermediate 15 (386 mg),tri(n-butyl)phosphine (747 μl), 2-(phenylsulfonyl)ethanol (359 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)-ethyl]ethylenediaminehydrochloride

Intermediate 24 (277 mg) was added with concentrated hydrochloric acid(5 ml) and stirred with heating at 90° C. for 48 hours. The reactionmixture was cooled to room temperature. The deposited precipitates werecollected by filtration and washed with ethanol to obtain the titlecompound (200 mg) as white powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.90-2.94 (2H, m), 3.42-3.47 (2H, m),3.50-3.57 (2H, m), 3.66-3.72 (2H, m), 6.98 (1H, d, J=7.5 Hz), 7.37 (1H,t, J=6.9 Hz), 7.60 (1H, t, J=7.8 Hz), 7.66-7.72 (2H, m), 7.78-7.83 (1H,m), 7.88 (2H, d, J=7.8 Hz), 7.94 (3H, br.s), 8.07 (1H, d, J=7.2 Hz),8.51 (1H, d, J=8.1 Hz), 11.73 (1H, d, J=5.4 Hz)

MS (m/z): 436 (MH+)

Example 13

N-[(1-Hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-352)

(Step A) Synthesis ofN-[(1-chloro-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-N-[2-(phenylsulfonyl)ethyl]propylenediamine(Intermediate 25)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1), thetitle compound (426 mg) was obtained from Intermediate 12 (400 mg),tri(n-butyl)phosphine (747 μl), 2-(phenylsulfonyl)ethanol (359 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)-ethyl]propylenediaminehydrochloride

Intermediate 25 (284 mg) was added with concentrated hydrochloric acid(5 ml) and stirred with heating at 90° C. for 48 hours. The reactionmixture was cooled to room temperature, and then the solvent wasevaporated under reduced pressure. The residue was added with ethanol (4ml). The deposited precipitates were collected by filtration and washedwith ethanol to obtain the title compound (206 mg) as white powderysolid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.69-1.79 (2H, m), 2.67-2.75 (2H, m),3.30-3.48 (4H, m), 3.56-3.62 (2H, m), 6.92 (1H, d, J=7.5 Hz), 7.35 (1H,dd, J=6.0, 7.5 Hz), 7.57 (1H, t, J=7.5 Hz), 7.65-7.72 (1H, m), 7.78-7.90(6H, m), 8.01 (1H, d, J=7.8 Hz), 8.49 (1H, d, J=7.8 Hz), 11.71 (1H, d,J=5.7 Hz)

MS (m/z): 450 (MH+)

Example 14

N-[(1-Hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-341)

(Step A) Synthesis ofN-[(1-chloro-5-isoquinolyl)sulfonyl]-N′-(tert-butoxycarbonyl)-N-(3-phenylpropyl)-1,3-propylenediamine(Intermediate 26)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (414 mg) was obtained from Intermediate 12 (400 mg),tri(n-butyl)phosphine (747 μl), 3-phenyl-1-propanol (405 μl) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis ofN-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediaminehydrochloride

According to the method of Example 13, Step B, the title compound (185mg) was obtained from Intermediate 26 (259 mg) as white powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.66-1.88 (4H, m), 2.40-2.46 (2H, m),2.71-2.77 (2H, m), 3.19-3.25 (2H, m), 3.20-3.38 (2H, m), 7.03-7.27 (6H,m), 7.36-7.40 (1H, m), 7.61 (1H, t, J=7.8 Hz), 7.94 (3H, bs.s), 8.16(1H, dd, J=0.9, 7.8 Hz), 8.49 (1H, d, J=8.1 Hz), 11.69 (1H, br.s)

MS (m/z): 400 (MH+)

Example 15

N-(5-Isoquinolyl)ethylenediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)ethylenediamine (Intermediate27)

Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (416 mg,Spex), tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), N-(2-aminoethyl)carbamicacid tert-butyl ester (385 mg) and sodium tert-butoxide (269 mg) intoluene (5 ml) was stirred with heating at 80° C. for 2 hours. Thereaction mixture was cooled to room temperature and added with ethylacetate (5 ml). The insoluble matters were removed by filtration throughCelite. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1) to obtain the title compound (402 mg).

(Step B) Synthesis of N-(5-isoquinolyl)ethylenediamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 27 (287 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (252 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 3.12-3.21 (2H, m), 3.55-3.60 (2H, m), 7.17(1H, d, J=7.8 Hz), 7.27 (1H, br.s), 7.68 (1H, d, J=8.1 Hz), 7.79 (1H,dd, J=7.8, 8.1 Hz), 8.30 (3H, br.s), 8.62 (1H, d, J=6.6 Hz), 8.84 (1H,d, J=6.6 Hz), 9.69 (1H, s)

MS (m/z): 188 (MH+)

Example 16

N-(5-Isoquinolyl)-1,3-propylenediamine hydrochloride (Exemplary CompoundNo. 2-1)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,3-propylenediamine(Intermediate 28)

According to the method of Example 15, Step A, the title compound (422mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), N-(3-aminopropyl)carbamicacid tert-butyl ester (418 mg) and sodium tert-butoxide (269 mg).

(Step B) Synthesis of N-(5-isoquinolyl)-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 28 (301 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (264 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.96-2.05 (2H, m), 2.90-3.00 (2H, m),3.37-3.45 (2H, m), 7.12 (1H, d, J=8.1 Hz), 7.27 (1H, br.s), 7.64 (1H, d,J=7.8 Hz), 7.78 (1H, dd, J=7.8, 8.1 Hz), 8.17 (3H, br.s), 8.59 (1H, d,J=6.9 Hz), 8.81 (1H, d, J=6.9 Hz), 9.69 (1H, s)

MS (m/z): 202 (MH+)

Example 17

N-(5-Isoquinolyl)-N′-methyl-1,3-propylenediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N-methyl-N′-(5-isoquinolyl)-1,3-propylenediamine(Intermediate 29)

Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (252 mg),tris(dibenzylideneacetone)palladium(0) (59 mg),2-(di-tert-butylphosphino)biphenyl (74 mg),(3-aminopropyl)methylcarbamic acid tert-butyl ester (274 mg, Asta Tech),and sodium tert-butoxide (163 mg) in toluene was stirred with heating at70° C. for 3 hours. The reaction mixture was returned to roomtemperature and purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to obtain the title compound (325 mg).

(Step B) Synthesis of N-(5-isoquinolyl)-N′-methyl-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 31 hours) by using Intermediate 29 (325 mg) and 10%hydrogen chloride/methanol solution (5 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(273 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.00-2.05 (2H, m), 2.47-2.51 (3H, m),2.95-2.99 (2H, m), 3.35-3.40 (2H, m), 7.10 (1H, d, J=7.5 Hz), 7.63 (1H,d, J=8.1 Hz), 7.75 (1H, t, J=8.1 Hz), 8.56 (1H, d, J=6.6 Hz), 8.84 (1H,d, J=6.6 Hz), 9.20 (1.5H, br.s), 9.69 (1H, s)

MS (m/z): 216 (MH+)

Example 18

N-(5-Isoquinolyl)-1,4-butylenediamine hydrochloride (Exemplary CompoundNo. 2-2)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,4-butylenediamine(Intermediate 30)

According to the method of Example 15, Step A, the title compound (442mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), N-(4-aminobutyl)carbamicacid tert-butyl ester (452 mg, Tokyo Kasei Kogyo) and sodiumtert-butoxide (269 mg).

(Step B) Synthesis of N-(5-isoquinolyl)-1,4-butylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 30 (316 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (276 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.80 (4H, m), 2.80-2.90 (2H, m),3.27-3.35 (2H, m), 7.11 (1H, d, J=7.8 Hz), 7.65 (1H, d, J=7.8 Hz), 7.78(1H, t, J=7.8 Hz), 8.20 (3H, br.s), 8.59 (1H, d, J=6.9 Hz), 8.91 (1H, d,J=6.9 Hz), 9.73 (1H, s)

MS (m/z): 216 (MH+)

Example 19

N-(5-Isoquinolyl)-pentamethylenediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-pentamethylenediamine(Intermediate 31)

Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (245 mg),tris(dibenzylideneacetone)palladium(0) (56 mg),2-(di-tert-butylphosphino)biphenyl (69 mg), N-(5-aminopentyl)carbamicacid tert-butyl ester (282 mg, Tokyo Kasei Kogyo) and sodiumtert-butoxide (160 mg) in toluene was stirred with heating at 70° C. for4.5 hours. The reaction mixture was cooled to room temperature andpurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (327 mg).

(Step B) Synthesis of N-(5-isoquinolyl)pentamethylenediaminehydrochloride

According to the method of the above Example, deprotection was performed(room temperature, 31 hours) by using Intermediate 31 (327 mg) and 10%hydrogen chloride/methanol solution (5 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(262 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.41-1.1.51 (2H, m), 1.59-1.75 (4H, m),2.72-2.79 (2H, m), 7.07 (1H, d, J=7.8 Hz), 7.62 (1H, d, J=8.1 Hz), 7.75(1H, t, J=8.1 Hz), 8.18 (3H, br.s), 8.55 (1H, d, J=6.6 Hz), 8.88 (1H, d,J=6.6 Hz), 9.70 (1H, s)

MS (m/z): 230 (MH+)

Example 20

4-(5-Isoquinolyl)aminopiperidine hydrochloride (Exemplary Compound No.2-4)

(Step A) Synthesis of4-(5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine (Intermediate32)

According to the method of Example 15, Step A, the title compound (327mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg),4-amino-1-(tert-butoxycarbonyl)piperidine (481 mg, Asta Tech) and sodiumtert-butoxide (269 mg).

(Step B) Synthesis of 4-(5-isoquinolyl)aminopiperidine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 32 (327 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (286 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.83-1.96 (2H, m), 2.10-2.20 (2H, m),2.99-3.11 (2H, m), 3.30-3.41 (2H, m), 3.82-3.91 (1H, m), 7.28 (1H, d,J=8.1 Hz), 7.70 (1H, d, J=8.1 Hz), 7.80 (1H, t, J=8.1 Hz), 8.60 (1H, d,J=6.9 Hz), 8.92 (1H, d, J=6.9 Hz), 9.32 (2H, br.s), 9.74 (1H, s)

MS (m/z): 228 (MH+)

Example 21

4-(5-Isbquinolyl)aminomethylpiperidine hydrochloride (Exemplary CompoundNo. 2-8)

(Step A) Synthesis of1-(tert-butoxycarbonyl)-4-(5-isoquinolyl)aminomethylpiperidine(Intermediate 33)

According to the method of Example 15, Step A, the title compound (260mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg),4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (514 mg, Asta Tech) andsodium tert-butoxide (269 mg).

(Step B) Synthesis of 4-(5-isoquinolyl)aminomethylpiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 33 (171 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (149 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.40-1.53 (2H, m), 1.92-2.11 (3H, m),2.76-2.88 (2H, m), 3.19-3.30 (4H, m), 7.12 (1H, d, J=7.8 Hz), 7.23 (1H,br.s), 7.62 (1H, d, J=8.1 Hz), 7.76 (1H, dd, J=7.8, 8.1 Hz), 8.59 (1H,d, J=6.6 Hz), 8.79 (1H, d, J=6.6 Hz), 8.83-9.16 (3H, br.s), 9.68 (1H, s)

MS (m/z): 242 (MH+)

Example 22

3-(5-Isoquinolyl)aminomethylpiperidine hydrochloride (Exemplary CompoundNo. 2-3)

(Step A) Synthesis of1-(tert-butoxycarbonyl)-3-(5-isoquinolyl)aminomethylpiperidine(Intermediate 34)

According to the method of Example 15, Step A, the title compound (249mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg),4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (514 mg, Asta Tech) andsodium tert-butoxide (269 mg).

(Step B) Synthesis of 3-(5-isoquinolyl)aminomethylpiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 34 (171 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (139 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.23-1.36 (1H, m), 1.63-1.96 (3H, m),2.21-3.30 (1H, m), 2.64-2.83 (2H, m), 3.15-3.36 (4H, m), 7.12 (1H, d,J=7.9 Hz), 7.26 (1H, br.s), 7.64 (1H, d, J=7.9 Hz), 7.76 (1H, t, J=7.9Hz), 8.59 (1H, d, J=6.7 Hz), 8.81 (1H, d, J=6.7 Hz), 8.98 (1H, br.s),9.32 (1H, br.s), 9.69 (1H, s)

MS (m/z): 242 (MH+)

Example 23

Cis-N-(5-Isoquinolyl)-1,4-cyclohexanediamine hydrochloride (ExemplaryCompound No. 2-5)

(Step A) Synthesis of trans-4-(N-tert-butoxycarbonylamino)cyclohexanol(Intermediate 35)

A solution of trans-4-aminocyclohexanol (50 g, Tokyo Kasei Kogyo) and 2N aqueous sodium hydroxide (200 ml) in 2-propanol (200 ml) was addedwith di-t-butyl dicarbonate (94.8 g, Wako Pure Chemical Industries) withstirring and ice cooling and stirred at room temperature for 4.5 hours.The reaction mixture was cooled again on ice and stirred for 1 hour.Then, the deposited crystals were collected by filtration, washed withwater and then dried at 40° C. under reduced pressure to obtain thetitle compound (90.3 g).

(Step B) Synthesis oftrans-N-(tert-butoxycarbonyl)-N-(4-methanesulfonyloxy-cyclohexyl)amine(Intermediate 36)

A solution of Intermediate 35 (90.3 g) in pyridine (415 ml) was addeddropwise with methanesulfonyl chloride (42.4 ml) with stirring and icecooling over 15 minutes and stirred with ice cooling for 30 minutes andat room temperature for 20 minutes. The reaction mixture was added withmethanol (54.2 ml) to terminate the reaction, stirred at roomtemperature for 2.5 hours, further added with water (540 ml) and stirredat room temperature for 1 hour and with ice cooling for 1 hour. Thedeposited precipitates were collected by filtration, washed with waterand then dried at 40° C. under reduced pressure to obtain the titlecompound (105 g).

(Step C) Synthesis of cis-4-(N-tert-butoxycarbonylamino)cyclohexyl azide(Intermediate 37)

A solution of Intermediate 36 (196 g) and trimethylsilyl azide (283 ml,Tokyo Kasei Kogyo) in dimethylformamide (667 ml) was added with cesiumfluoride (305 g, Wako Pure Chemical Industries) with stirring andstirred at 70° C. for 4 days. The reaction mixture was cooled to roomtemperature and then added twice with water in a volume of 2.75 l intotal. This reaction mixture was stirred with ice cooling for 2 hours,and the deposited precipitates were collected by filtration. Then, theprecipitates were washed with water to obtain a roughly purified productof the title compound (142 g).

(Step D) Synthesis of cis-4-(N-tert-butoxycarbonylamino)cyclohexylamine(Intermediate 38)

The roughly purified product of Intermediate 37 (142 g) was reduced byhydrogenation at room temperature for 9 hours by using 10% Pd/C (7.1 g)and ethyl acetate solution (1.42 l) under hydrogen atmosphere of 1 atm.The palladium catalyst was removed by filtration, and the solvent wasevaporated under reduced pressure. Then, the residue was purified byflash column chromatography(chloroform:methanol:triethylamine=100:20:10) to obtain the titlecompound (45.8 g).

(Step E) Synthesis ofcis-N-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 39)

Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (253 mg),tris(dibenzylideneacetone)palladium(0) (58 mg),2-(di-tert-butylphosphino)biphenyl (74 mg), Intermediate 38 (311 mg) andsodium tert-butoxide (165 mg) in toluene was stirred with heating at 70°C. for 3 hours. The reaction mixture was cooled to room temperature andpurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (320 mg).

(Step F) Synthesis of cis-N-(5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 31 hours) by using Intermediate 39 (214 mg) and 10%hydrogen chloride/methanol solution (5 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(215 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-2.05 (8H, m), 2.49 (2H, s), 3.05-3.23(1H, m), 3.70-3.80 (1H, m), 7.15 (1H, d, J=7.8 Hz), 7.67 (1H, d, J=7.8Hz), 7.78 (1H, t, J=7.8 Hz), 8.18 (2H, br.s), 8.60 (1H, d, J=6.6 Hz),8.90 (1H, d, J=6.9 Hz), 9.71 (1H, s)

MS (m/z): 242 (MH+)

Example 24

Trans-N-(5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride (ExemplaryCompound No. 2-6)

(Step A) Synthesis oftrans-4-(N-tert-butoxycarbonylamino)cyclohexylamine (Intermediate 40)

A solution of trans-1,4-cyclohexanediamine (25 g, Tokyo Kasei Kogyo) ina mixed solvent of water (437 ml) and t-butyl alcohol (512 ml) was addedwith 2.5 N aqueous sodium hydroxide (30 ml), added dropwise withdi-t-butyl dicarbonate (23.9 g) with ice cooling and stirred at roomtemperature for 15 hours. The reaction mixture was concentrated underreduced pressure, added with water and extracted with dichloromethane,and the organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate:methanol=10:1) to obtain the title compound (12.9 g).

(Step B) Synthesis oftrans-N-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 41)

Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (100 mg),tris(dibenzylideneacetone)palladium(0) (23 mg),2-(di-tert-butylphosphino)biphenyl (29 mg), Intermediate 40 (122 mg) andsodium tert-butoxide (66 mg) in toluene was stirred with heating at 70°C. for 3.5 hours. The reaction mixture was cooled to room temperatureand purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (69 mg).

(Step C) Synthesis of trans-N-(5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 1 hour) by using Intermediate 41 (69 mg) and 10% hydrogenchloride/methanol solution (4 ml). The solvent was evaporated underreduced pressure, and the residue was added with methanol (0.5 ml) anddiethyl ether (2 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(58.7 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.35-1.62 (4H, m), 1.95-2.20 (4H, m), 2.49(1H, t, J=1.8 Hz), 2.90-3.10 (1H, m), 3.40-3.52 (1H, m), 7.21 (1H, d,J=8.1 Hz), 7.63 (1H, d, J=8.1 Hz), 7.75 (1H, t, J=8.1 Hz), 8.31 (2H,br.s), 8.56 (1H, d, J=6.6 Hz), 8.84 (1H, d, J=6.9 Hz), 9.70 (1H, s)

MS (m/z): 242 (MH+)

Example 25

N-(5-Isoquinolyl)-1,3-cyclohexanediamine hydrochloride (ExemplaryCompound No. 2-7)

(Step A) Synthesis of N-(tert-butoxycarbonyl)-1,3-cyclohexanediamine(Intermediate 42)

According to the method of Example 24, Step A, the title compound (3.8g) was obtained from 1,3-cyclohexanediamine (11.4 g, Tokyo Kasei Kogyo)and di-tert-butyl dicarbonate (10.9 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,3-cyclohexanediamine(Intermediate 43)

According to the method of Example 15, Step A, the title compound (273mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), Intermediate 42 (514 mg,synthesized according to Example 24, Step A) and sodium tert-butoxide(269 mg).

(Step C) Synthesis of N-(5-isoquinolyl)-1,3-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 43 (171 mg) and 10% hydrogenchloride/methanol solution (2.5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (149 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.24-2.40 (8H, m), 3.15-4.15 (2H, m), 7.25(1H, d, J=7.8 Hz), 7.68 (1H, m), 7.81 (1H, m), 8.22 (1H, br.s), 8.58(1H, d, J=6.9 Hz), 8.84 (1H, m), 9.72 (1H, s)

MS (m/z): 242 (MH+)

Example 26

N-(5-Isoquinolyl)-1,3-xylylenediamine hydrochloride (Exemplary CompoundNo. 2-11)

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(5-isoquinolyl)-1,3-xylylenediamine(Intermediate 44)

According to the method of Example 15, Step A, the title compound (508mg) was obtained under nitrogen atmosphere from 5-bromoisoquinoline (416mg), tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg),N-(tert-butoxycarbonyl)-1,3-xylylenediamine (567 mg, Asta Tech) andsodium tert-butoxide (269 mg).

(Step B) Synthesis of N-(5-isoquinolyl)-1,3-xylylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 44 (364 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (316 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 3.96-4.01 (2H, m), 4.57 (2H, s), 6.91 (1H, dd,J=1.5, 7.8 Hz), 7.34-7.44 (3H, m), 7.57-7.69 (3H, m), 7.95 (1H, br.s),8.51 (3H, br.s), 8.63 (1H, d, J=6.9 Hz), 8.85 (1H, d, J=6.9 Hz), 9.69(1H, s)

MS (m/z): 264 (MH+)

Example 27

4-[(5-Isoquinolyl)oxy]piperidine hydrochloride (Exemplary Compound No.1-2)

(Step A) Synthesis of1-(tert-butoxycarbonyl)-4-[(5-isoquinolyl)oxy]piperidine (Intermediate45)

According to the method of Example 10, Step A with the modificationsthat the reaction was carried out for 48 hours, and the compound waspurified by silica gel column chromatography (n-hexane:ethylacetate=3:1), the title compound (213 mg) was obtained from5-hydroxyisoquinoline (145 mg, Aldrich), tri(n-butyl)phosphine (747 μl),1-(tert-butoxycarbonyl)-4-hydroxypiperidine (604 mg, Aldrich) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step B) Synthesis of 4-[(5-isoquinolyl)oxy]piperidine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 45 (164 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (128 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.00-2.13 (2H, m), 2.19-2.32 (2H, m),3.08-3.21 (2H, m), 3.25-3.39 (2H, m), 5.03-5.11 (1H, m), 7.77 (1H, d,J=7.5 Hz), 7.93 (1H, t, J=8.1 Hz), 8.08 (1H, d, J=8.4 Hz), 8.58 (1H, d,J=6.6 Hz), 8.65 (1H, d, J=6.6 Hz), 9.44 (2H, br.s), 9.86 (1H, s)

MS (m/z): 229 (MH+)

Example 28

4-[N-(5-Isoquinolyl)-N-methyl]aminopiperidine hydrochloride (ExemplaryCompound No. 2-114)

(Step A) Synthesis of 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine(Intermediate 46)

A solution of methylamine hydrochloride (1.01 g, Wako Pure ChemicalIndustries) and 1-(tert-butoxycarbonyl)-4-oxopiperidine (1.99 g,Aldrich) in methanol (13 ml) was stirred in the presence of platinumoxide (69 mg, Wako Pure Chemical Industries) at room temperature for 3hours under hydrogen atmosphere of ordinary pressure. The hydrogen waspurged with a nitrogen gas, and the platinum catalyst was removed byfiltration. Then, the reaction mixture was adjusted to pH of from 10 to11 with 1 N aqueous sodium hydroxide. The reaction mixture was addedwith water (10 ml), and the product was extracted three times with ethylacetate (15 ml for each time). The organic layer was dried overanhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:methanol=20:1) to obtain the titlecompound (2.01 g).

(Step B) Synthesis of1-(tert-butoxycarbonyl)-4-[N-(5-isoquinolyl)-N-methyl]aminopiperidine(Intermediate 47)

According to the method of Example 15, Step A, the title compound (88mg) was obtained from 5-bromoisoquinoline (416 mg),tris(dibenzylideneacetone)dipalladium(0) (92 mg),2-(di-tert-butylphosphino)biphenyl (119 mg), Intermediate 46 (515 mg)and sodium tert-butoxide (269 mg).

(Step C) 4-[N-(5-isoquinolyl)-N-methyl]aminopiperidine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 47 (68 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (0.5 ml) and diethyl ether(1.5 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (56 mg) as lightyellow powdery solid.

MS (m/z): 242 (MH+)

Example 29

3-N-(5-Isoquinolyl)aminopiperidine hydrochloride (Exemplary Compound No.2-10)

(Step A) Synthesis of1-N-(tert-butoxycarbonyl)-3-N′-(5-isoquinolyl)aminopiperidine(Intermediate 48)

According to the method of Example 15, Step A, the title compound (437mg) was obtained under nitrogen atmosphere from 5-bromoisoquinoline (300mg), tris(dibenzylideneacetone)dipalladium(0) (69 mg),2-(di-tert-butylphosphino)biphenyl (86 mg),(+/−)-3-amino-1-N-(tert-butoxycarbonyl)piperidine (341 mg, Asta Tech)and sodium tert-butoxide (197 mg).

(Step B) Synthesis of 3-N-(5-isoquinolyl)aminopiperidine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 3 hours) by using Intermediate 48 (195 mg) and 10%hydrogen chloride/methanol solution (4 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(131 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.93 (1H, m), 1.95-2.02 (2H, m),2.06-2.20 (1H, m), 3.16-3.26 (2H, m), 3.65 (2H, d, J=6.0 Hz), 3.87-3.91(1H, m), 7.23 (1H, d, J=7.5 Hz), 7.49 (1H, br.s), 7.69 (1H, d, J=8.1Hz), 7.78 (1H, dd, 7.8 Hz), 8.62 (1H, d, J=6.6 Hz), 8.91 (1H, d, J=6.9Hz), 9.44 (1H, br.s), 9.71 (1H, s), 9.78 (1H, s)

MS (m/z): 228 (MH+)

Examples 30 to 102

According to the method of Example 1, Step B, Intermediates 64 to 70(amines) obtained in Reference Examples 9 to 15 were used to perform theMitsunobu reaction with an alcohol suitably selected from alcohols(al-1) to (al-11). The obtained crowns were allowed to act on a mixedsolvent of trifluoroacetic acid and dichloromethane (1/1) and therebyobtained the compounds of Examples 30 to 102 listed in Table 4 shownbelow. The compound of each example showed a peak of MH+ in the massspectrum as expected. The compounds listed in Table 4 are represented bythe following formula (1a). In the formula (1a), substituents are asshown in the following tables. TABLE 4 (1a)

Compound of Exemplary Reagent Example Compound Example No. Alcohol Amine—ak -an No. 30 al-1 am-1 ak-1 an-1 3-1 31 al-2 am-1 ak-2 an-1 3-2 32al-3 am-1 ak-3 an-1 3-3 33 al-4 am-1 ak-4 an-1 3-4 34 al-5 am-1 ak-5an-1 3-5 35 al-6 am-1 ak-6 an-1 3-6 36 al-7 am-1 ak-7 an-1 3-7 37 al-8am-1 ak-8 an-1 3-8 38 al-9 am-1 ak-9 an-1 3-9 39 al-10 am-1 ak-10 an-13-11 40 al-2 am-2 ak-2 an-2 3-36 41 al-4 am-2 ak-4 an-2 3-38 42 al-5am-2 ak-5 an-2 3-39 43 al-6 am-2 ak-6 an-2 3-40 44 al-7 am-2 ak-7 an-23-41 45 al-8 am-2 ak-8 an-2 3-42 46 al-9 am-2 ak-9 an-2 3-43 47 al-10am-2 ak-10 an-2 3-45 48 al-1 am-3 ak-1 an-3 3-69 49 al-2 am-3 ak-2 an-33-70 50 al-3 am-3 ak-3 an-3 3-71 51 al-4 am-3 ak-4 an-3 3-72 52 al-5am-3 ak-5 an-3 3-73 53 al-6 am-3 ak-6 an-3 3-74 54 al-7 am-3 ak-7 an-33-75 SS al-8 am-3 ak-8 an-3 3-76 56 al-9 am-3 ak-9 an-3 3-77 57 al-10am-3 ak-10 an-3 3-79 58 al-11 am-3 ak-1l an-3 3-80 59 al-1 am-4 ak-1an-4 3-137 60 al-2 am-4 ak-2 an-4 3-138 61 al-3 am-4 ak-3 an-4 3-139 62al-4 am-4 ak-4 an-4 3-140 63 al-5 am-4 ak-5 an-4 3-141 64 al-6 am-4 ak-6an-4 3-142 65 al-7 am-4 ak-7 an-4 3-143 66 al-8 am-4 ak-8 an-4 3-144 67al-9 am-4 ak-9 an-4 3-145 68 al-10 am-4 ak-10 an-4 3-147 69 al-11 am-4ak-11 an-4 3-148 70 al-1 am-5 ak-1 an-5 3-171 71 al-2 am-5 ak-2 an-53-172 72 al-3 am-5 ak-3 an-5 3-173 73 al-5 am-5 ak-4 an-5 3-174 74 al-5am-5 ak-5 an-5 3-175 7S al-6 am-5 ak-6 an-5 3-176 76 al-7 am-5 ak-7 an-53-177 77 al-8 am-5 ak-8 an-5 3-178 78 al-9 am-5 ak-9 an-5 3-179 79 al-10am-5 ak-10 an-5 3-181 80 al-11 am-5 ak-11 an-5 3-182 81 al-1 am-6 ak-1an-6 3-239 82 al-2 am-6 ak-2 an-6 3-240 83 al-3 am-6 ak-3 an-6 3-241 84al-4 am-6 ak-4 an-6 3-242 85 al-5 am-6 ak-5 an-6 3-243 86 al-6 am-6 ak-6an-6 3-244 87 al-7 am-6 ak-7 an-6 3-245 88 al-8 am-6 ak-8 an-6 3-246 89al-9 am-6 ak-9 an-6 3-247 90 al-10 am-6 ak-10 an-6 3-249 91 al-11 am-6ak-11 an-6 3-250 92 al-1 am-7 ak-1 an-7 3-273 93 al-2 am-7 ak-2 an-73-274 94 aI-3 am-7 ak-3 an-7 3-275 95 aI-4 am-7 ak-4 an-7 3-276 96 al-5am-7 ak-5 an-7 3-277 97 al-6 am-7 ak-6 an-7 3-278 98 al-7 am-7 ak-7 an-73-279 99 al-B am-7 ak-8 an-7 3-280 100 al-9 am-7 ak-9 an-7 3-281 101al-10 am-7 ak-10 an-7 3-283 102 al-11 am-7 ak-1l an-7 3-284Table 4 mentioned above, an-1 to an-7 are the following groups.

Tables 15 and 16 mentioned above, ak-1 to ak-11 are the followinggroups.

The alcohols (al-1) to (al-11) used in Examples 30 to 102 were asfollows.

al-1 is 3-phenyl-1-propanol (Tokyo Kasei Kogyo), al-2 is phenethylalcohol (Tokyo Kasei Kogyo), al-3 is 2-(2-thienyl)ethanol (Aldrich),al-4 is 2-(3-thienyl)ethanol (Aldrich), al-5 is 4-chlorophenethylalcohol (Tokyo Kasei Kogyo), al-6 is 2-(phenylthio)ethanol (Aldrich),al-7 is 4-fluorophenethyl alcohol (Aldrich), al-8 is 3-phenyl-1-butanol(Aldrich), al-9 is 2-cyclopentylethanol (Tokyo Kasei Kogyo), al-10 is2-fluorophenethyl alcohol (Aldrich), and al-11 is2-(phenylsulfonyl)ethanol.

The amines (am-1) to (am-7) used in Example 30 to 102 are as follows.

am-1 is Intermediate 64, am-2 is Intermediate 65, am-3 is Intermediate66, am-4 is Intermediate 67, am-5 is Intermediate 68, am-6 isIntermediate 69, and am-7 is Intermediate 70.

Example 103

4-(4-Bromo-5-isoquinolylaminopiperidine hydrochloride (ExemplaryCompound No. 2-181)

(Step A) Synthesis of4-(4-bromo-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 71)

A mixture of 4-bromo-5-aminoisoquinoline (3.00 g) obtained in ReferenceExample 1 and tert-butyl 4-oxo-1-piperidinecarboxylate (5.50 g, Aldrich)was added with titanium tetraisopropoxide (8.20 ml, Aldrich) at roomtemperature and stirred at room temperature for 15 hours. Subsequently,the reaction mixture was added with methanol (60 ml) and sodiumborohydride (2.21 g, Kanto Chemicals) and further stirred at roomtemperature for 19 hours. The reaction mixture was added with saturatedaqueous sodium hydrogencarbonate (100 ml) and ethyl acetate (100 ml),stirred for 0.5 hour and filtered through Celite, and the solvent wasevaporated under reduced pressure. The residue was added with ethylacetate (100 ml) and washed twice with saturated aqueous sodiumhydrogencarbonate (50 ml for each time), and the organic layer was driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:acetone:isopropylamine=150:10:2) to obtain thetitle compound (2.92 g).

(Step B) Synthesis of 4-(4-bromo-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 71 (123 mg) and 10% hydrogenchloride/methanol solution (6 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (52 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.85 (2H, m), 2.20-2.24 (2H, m),3.02-3.13 (2H, m), 3.28-3.33 (2H, m), 3.79-3.86 (1H, m), 7.16 (1H, d,J=7.9 Hz), 7.53 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=7.9 Hz), 8.58 (1H, s),9.00-9.18 (1H, br.s), 9.26 (1H, s)

MS (m/z): 306 (MH+)

Example 104

4-(4-Fluoro-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-103)

(Step A) Synthesis of4-(4-fluoro-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 72)

A solution of Intermediate 71 (104 mg) in dimethyl sulfoxide (2 ml) wasadded with cesium fluoride (284 mg, Wako Pure Chemical Industries) andstirred at 150° C. for 8 hours. The reaction mixture was cooled to roomtemperature and then filtered through Celite. The residue was added withwater (20 ml), extracted with ethyl acetate (20 ml) and washed twicewith saturated brine (10 ml for each time). The organic layer was driedover anhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound(21.1 mg).

(Step B) Synthesis of 4-(4-fluoro-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 72 (30.2 mg) and 10% hydrogenchloride/methanol solution (3 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (18.1 mg) aslight yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.70-1.84 (2H, m), 2.16-2.20 (2H, m),2.98-3.10 (2H, m), 3.29-3.34 (2H, m), 3.80-3.82 (1H, m), 7.12 (1H, d,J=8.0 Hz), 7.51-7.54 (1H, m), 7.65 (1H, d, J=8.0 Hz), 8.43 (1H, d, J=6.1Hz), 8.90-9.10 (1H, m), 9.20 (1H, s)

MS (m/z): 246 (MH+)

Example 105

4-(4-Methylthio-5-isoquinolyl)aminopiperidine hydrochloride

(Step A) Synthesis of 5-amino-4-methylthioisoquinoline (Intermediate 73)

A solution of 4-bromo-5-aminoisoquinoline (1.04 g) obtained in ReferenceExample 1 in N,N-dimethylformamide (10 ml) was added withmethylmercaptan sodium salt (1.38 g, Aldrich) and stirred at 100° C. for16 hours. The reaction mixture was cooled to room temperature andfiltered through Celite. The residue was added with ethyl acetate (100ml) and washed three times with saturated brine (50 ml for each time).The organic layer was dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1) toobtain the title compound (225 mg).

(Step B) Synthesis of4-(4-methylthio-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 74)

According to the method of Example 103, Step A with the modificationsthat the reaction was carried out for 72 hours, and the compound waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1), the title compound (256 mg) was obtained from Intermediate73 (225 mg), tert-butyl 4-oxo-1-piperidinecarboxylate (484 mg), titaniumtetraisopropoxide (720 μl) and sodium borohydride (195 mg).

(Step C) Synthesis of 4-(4-methylthio-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 74 (214 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (154 mg) as brownpowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.70-1.85 (2H, m), 2.18-2.24 (2H, m), 2.62(3H, s), 3.01-3.13 (2H, m), 3.29-3.34 (2H, m), 3.78-3.82 (1H, m), 7.14(1H, br.s), 7.24 (1H, d, J=7.2 Hz), 7.60-7.72 (2H, m), 8.31 (1H, s),8.99 (1H, br.s), 9.09 (1H, br.s), 9.34 (1H, s)

MS (m/z): 274 (MH+)

Example 106

4-(4-Methyl-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-70)

(Step A) Synthesis of4-(4-methyl-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 75)

A solution of Intermediate 71 (313 mg) in toluene (6 ml) was added withtetrakis(triphenylphosphine)palladium(0) (17.9 mg, Aldrich),tetramethyltin (165 μl, Kanto Chemicals) and2,6-di-tert-butyl-4-methylphenol (several pellets, Tokyo Kasei Kogyo)and stirred in a sealed tube at 150° C. for 48 hours. The reactionmixture was cooled to room temperature, filtered through Celite andconcentrated under reduced pressure. The residue was added withsaturated brine (30 ml) and extracted three times with ethyl acetate (30ml for each time). The organic layers were combined and dried overanhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) to obtain the title compound(61.7 mg).

(Step B) Synthesis of 4-(4-methyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 75 (90.7 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (90.4 mg) aslight yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.80-1.90 (2H, m), 2.16-2.21 (2H, m),3.04-3.16 (5H, m), 3.27-3.31 (2H, m), 3.73-3.80 (1H, m), 7.37-7.41 (1H,m), 7.74-7.81 (2H, m), 8.30 (1H, s), 9.17-9.20 (1H, m), 9.35-9.39 (1H,m), 9.57 (1H, s)

MS (m/z): 242 (MH+)

Example 107

N-(4-Bromo-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-bromo-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 76)

According to the method of Example 103, Step A, the title compound (942mg) was obtained from 4-bromo-5-aminoisoquinoline (1.02 g) obtained inReference Example 1, tert-butyl 4-oxo-1-aminocyclohexylcarboxylate (1.95g, Asta Tech), titanium tetraisopropoxide (2.78 ml) and sodiumborohydride (752 mg).

(Step B) Synthesis of N-(4-bromo-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 76 (124 mg) and 10% hydrogenchloride/methanol solution (3 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (107 mg).

MS (m/z): 320 (MH+)

Example 108

N-(4-Fluoro-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-fluoro-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 77)

According to Example 104, Step A, the title compound (90.8 mg) wasobtained from Intermediate 76 (125 mg) and cesium fluoride (316 mg).

(Step B) Synthesis of N-(4-fluoro-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 77 (90.8 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (75.4 mg).

MS (m/z): 260 (MH+)

Example 109

N-(4-Methylthio-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-methylthio-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 78)

According to the method of Example 103, Step A, the title compound (341mg) was obtained from Intermediate 73 (270 mg), tert-butyl4-oxo-1-aminocyclohexylcarboxylate (605 mg), titanium tetraisopropoxide(864 μl) and sodium borohydride (233 mg).

(Step B) Synthesis ofN-(4-methylthio-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 78 (341 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (279 mg).

MS (m/z): 288 (MH+)

Example 110

4-(4-Methanesulfinyl-5-isoquinolyl)aminopip eridine hydrochloride

(Step A) Synthesis of4-(4-methanesulfinyl-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 79)

Intermediate 74 (746 mg) obtained in Example 105, Step B was added withacetic acid (1.5 ml) and 30% aqueous hydrogen peroxide (2 ml) andstirred at room temperature for 17 hours. The reaction mixture was addedwith ethyl acetate (50 ml) and washed three times with saturated aqueoussodium hydrogencarbonate (25 ml for each time), and the organic layerwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (n-hexane:acetone=3:1) to obtain the titlecompound (390 mg).

(Step B) Synthesis of 4-(4-methanesulfinyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 79 (138 mg) and 10% hydrogenchloride/methanol solution (3 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (92.2 mg) asbrown powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.83 (2H, m), 2.12-2.24 (2H, m), 2.81(3H, s), 3.00-3.12 (2H, m), 3.25-3.38 (2H, m), 3.66-3.78 (1H, m), 6.54(1H, br.s), 7.37-7.40 (1H, m), 7.71-7.75 (2H, m), 8.79 (1H, s), 8.87(1H, br.s), 9.06 (1H, br.s), 9.54 (1H, s)

MS (m/z): 290 (MH+)

Example 111

4-(4-Methanesulfonyl-5-isoquinolyl)aminopiperidine hydrochloride(Exemplary Compound No. 2-48)

(Step A) Synthesis of4-(4-methanesulfonyl-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 80)

Intermediate 74 (746 mg) obtained in Example 105, Step B was added withacetic acid (1.5 ml) and 30% aqueous hydrogen peroxide (2 ml) andstirred at room temperature for 17 hours. The reaction mixture was addedwith ethyl acetate (50 ml) and washed three times with saturated aqueoussodium hydrogencarbonate (25 ml for each time), and the organic layerwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (n-hexane:acetone=4:1) to obtain the titlecompound (40.9 mg).

(Step B) Synthesis of 4-(4-methanesulfonyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 80 (40.9 mg) and 10% hydrogenchloride/methanol solution (1 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (11.4 mg) asbrown powdery solid.

MS (m/z): 306 (MH+)

Example 112

4-(4-Vinyl-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-203)

(Step A) Synthesis of4-(4-vinyl-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 81)

According to the method of Example 106, Step A, the title compound (1.55g) was obtained from Intermediate 71 (2.31 g),tetrakis(triphenylphosphine)palladium(0) (131 mg), tri(n-butyl)vinyltin(2.60 ml, Tokyo Kasei Kogyo) and 2,6-di-tert-butyl-4-methylphenol(several pellets).

(Step B) Synthesis of 4-(4-vinyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 81 (46.6 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (25.3 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.81 (2H, m), 2.10-2.21 (2H, m),2.98-3.10 (2H, m), 3.23-3.30 (2H, m), 3.70-3.81 (1H, m), 5.54 (1H,br.s), 5.70 (1H, m), 5.81 (1H, m), 7.30 (1H, dd, J=2.3, 6.5 Hz),7.60-7.77 (3H, m), 8.26 (1H, s), 9.00 (1H, br.s), 9.18 (1H, br.s), 9.52(1H, s)

MS (m/z): 254 (MH+)

Example 113

4-(4-Ethyl-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-192)

(Step A) Synthesis of4-(4-ethyl-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 82)

A solution (2 ml) of Intermediate 81 (103 mg) in methanol was vigorouslystirred in the presence of 10% palladium carbon catalyst (16.5 mg) atroom temperature under hydrogen atmosphere of ordinary pressure. Thereaction mixture was filtered through Celite, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to obtain the titlecompound (93.7 mg).

(Step B) Synthesis of 4-(4-ethyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 82 (93.7 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (63.2 mg) aslight yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.24 (3H, t, J=7.3 Hz), 1.71-1.86 (2H, m),2.18-2.22 (2H, m), 3.01-3.17 (2H, m), 3.38-3.42 (2H, m), 3.70-3.78 (1H,m), 5.82 (1H, br.s), 7.36-7.39 (1H, m), 7.74-7.75 (2H, m), 8.28 (1H, s),8.85 (1H, br.s), 9.05 (1H, br.s), 9.49 (1H, s)

MS (m/z): 256 (MH+)

Example 114

4-(1-Chloro-5-isoquinolyl)aminopiperidine trifluoroacetate

(Step A) Synthesis of 1-chloro-5-aminoisoquinoline (Intermediate 83)

A solution (40 ml) of 1-chloro-5-nitroisoquinoline (2.23 g, synthesizedaccording to the method described in J. Med. Chem. 45, 3, 740 (2002)) inethyl acetate was added with tin(II) chloride dihydrate (12.39 g, WakoPure Chemical Industries) at room temperature and stirred with heatingat 70° C. for 1 hour. The reaction mixture was cooled to roomtemperature, then added with ice (200 g) and stirred for 0.5 hour. Thereaction mixture was filtered through Celite and extracted three timeswith ethyl acetate (200 ml for each time), and the organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound(749 mg).

(Step B) Synthesis of4-(1-chloro-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)-piperidine(Intermediate 84)

According to the method of Example 103, Step A, the title compound (846mg) was obtained from Intermediate 83 (749 mg), tert-butyl4-oxo-1-piperidinecarboxylate (1.72 g), titanium tetraisopropoxide (2.60ml) and sodium borohydride (691 mg).

(Step C) Synthesis of 4-(1-chloro-5-isoquinolyl)aminopiperidinetrifluoroacetate

Deprotection was performed (room temperature, 2 hours) by usingIntermediate 84 (81.9 mg) and a mixed solution of trifluoroacetic acidand methylene chloride (1:1, 2 ml). The solvent was evaporated underreduced pressure, and the residue was added with methanol (2 ml) anddiethyl ether (6 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(64 mg) as yellow powdery crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.82 (2H, m), 2.09-2.19 (2H, m),3.02-3.13 (2H, m), 3.37-3.41 (2H, m), 3.70-3.80 (1H, m), 6.40 (1H,br.s), 6.97 (1H, d, J=7.7 Hz), 7.46 (1H, d, J=8.3 Hz), 7.57 (1H, t,J=8.1 Hz), 8.19-8.24 (2H, m), 8.58 (1H, br.s), 8.73 (1H, br.s)

MS (m/z): 262 (MH+)

Example 115

4-(1-Hydroxy-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-59)

Intermediate 84 (76.6 mg) was added with concentrated hydrochloric acid(1.5 ml) and stirred with heating at 85° C. for 7 hours. The reactionmixture was cooled to room temperature, and then the residue was addedwith ethanol (1 ml) and diethyl ether (2 ml). The deposited precipitateswere collected by filtration and washed with diethyl ether to obtain thetitle compound (55.5 mg) as white powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.70-1.81 (2H, m), 2.07-2.11 (2H, m),2.95-3.06 (2H, m), 3.30-3.34 (2H, m), 3.63-3.70 (1H, m), 6.87-6.94 (2H,m), 7.07-7.11 (1H, m), 7.27 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=8.1 Hz),8.87 (1H, br.s), 9.00 (1H, br.s), 11.20 (1H, br.s),

MS (m/z): 244 (MH+)

Example 116

N-(4-Vinyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 85)

According to the method of Example 106, Step A, the title compound (222mg) was obtained from Intermediate 76 (302 mg),tetrakis(triphenylphosphine)palladium(0) (16.8 mg), tri(n-butyl)vinyltin(328 μl) and 2,6-di-tert-butyl-4-methylphenol (several pellets).

(Step B) Synthesis of N-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 85 (85.5 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (52.3 mg).

MS (m/z): 268 (MH+)

Example 117

N-(4-Ethyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 86)

According to the method of Example 113, Step A, the title compound (133mg) was obtained from Intermediate 85 (152 mg) and 10% palladium carboncatalyst (14.0 mg).

(Step B) Synthesis of N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 86 (133 mg) and 10% hydrogenchloride/methanol solution (2 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (80.9 mg).

MS (m/z): 270 (MH+)

Example 118

4-(4-Chloro-5-isoquinolyl)aminopiperidine hydrochloride

(Step A) Synthesis of 4-aminoisoquinoline (Intermediate 87)

A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfatepentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and1,4-dioxane (100 ml) was stirred in a sealed tube at 165° C. for 21hours. The reaction mixture was cooled to room temperature, theinsoluble matters were removed by filtration through Celite, and thefiltrate was extracted twice with ethyl acetate (150 ml for each time).The organic layer was dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (chloroform:methanol=9:1) to obtainthe title compound (13.2 g).

(Step B) Synthesis of 4-chloroisoquinoline (Intermediate 88)

Intermediate 87 (1.27 g) was dissolved in 1 N aqueous hydrochloric acid(36 ml) and added dropwise with an aqueous solution (36 ml) of sodiumnitrite (1.21 g, Wako Pure Chemical Industries) with ice cooling. Theobtained suspension was added dropwise to a solution of copper(I)chloride (1.83 g, Wako Pure Chemical Industries) in 1 N aqueoushydrochloric acid (20 ml) with ice cooling, then warmed to roomtemperature and stirred for 15 hours. The reaction mixture was addedwith 28% aqueous ammonia (50 ml) and extracted twice with ethyl acetate(150 ml for each time). The organic layer was dried over anhydroussodium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1) to obtain the title compound (433 mg).

(Step C) Synthesis of 4-chloro-5-nitroisoquinoline (Intermediate 89)

Intermediate 88 (375 mg) was dissolved in concentrated sulfuric acid (2ml), then added with potassium nitrate (260 mg) with ice cooling andstirred for 2 hours. The reaction mixture was added with 28% aqueousammonia (10 ml) and extracted twice with ethyl acetate (15 ml for eachtime). The organic layer was dried over anhydrous sodium sulfate, andthen the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (332 mg).

(Step D) Synthesis of 4-chloro-5-aminoisoquinoline (Intermediate 90)

Tin(II) chloride dihydrate (1.70 g) was dissolved in concentratedhydrochloric acid (1 ml), added with a mixture of Intermediate 89 (315mg) and 2 N aqueous hydrochloric acid (2 ml) with ice cooling andrefluxed with heating for 2 hours. The reaction mixture was cooled toroom temperature, added with 5 N aqueous sodium hydroxide (7 ml) andextracted twice with chloroform (20 ml for each time). The organic layerwas dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to obtain the title compound (182 mg).

(Step E) Synthesis of4-(4-chloro-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 91)

According to the method of Example 103, Step A, a mixture ofIntermediate 90 (121 mg), tert-butyl 4-oxo-1-piperidinecarboxylate (274mg), titanium tetraisopropoxide (0.41 ml) and dichloromethane (7 ml) wasstirred at room temperature for 138 hours. The reaction mixture wasadded with sodium borohydride (114 mg) and methanol (1 ml) and stirredfor 1.5 hours with ice cooling. The reaction mixture was added withsaturated aqueous sodium hydrogencarbonate (10 ml) with ice cooling andextracted twice with ethyl acetate (15 ml for each time). The organiclayer was dried over anhydrous sodium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=1:1) to obtain thetitle compound (53.5 mg).

(Step F) Synthesis of 4-(4-chloro-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 91 (53.5 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(50.8 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.92 (2H, m), 2.18-2.24 (2H, m),3.01-3.09 (2H, m), 3.27-3.32 (2H, m), 3.78-3.85 (1H, m), 7.20 (1H, d,J=7.9 Hz), 7.58 (1H, d, J=8.1 Hz), 7.67 (1H, t, J=7.9 Hz), 8.48 (1H, s),9.17 (1H, s), 9.32 (2H, br.s)

MS (m/z): 262 (MH+)

Example 119

N-(4-Chloro-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-chloro-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 92)

According to the method of Example 103, Step A, a mixture ofIntermediate 90 (100 mg), tert-butyl 4-oxo-1-aminocyclohexylcarboxylate(270 mg), titanium tetraisopropoxide (0.34 ml) and dichloromethane (7ml) was stirred at room temperature for 120 hours. The reaction mixturewas added with sodium borohydride (94 mg) and methanol (1 ml) andstirred for 1.5 hours with ice cooling. The reaction mixture was addedwith saturated aqueous sodium hydrogencarbonate (10 ml) with ice coolingand then extracted twice with ethyl acetate (15 ml for each time). Theorganic layer was dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1) toobtain the title compound (40.4 mg).

(Step B) Synthesis of N-(4-chloro-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 92 (40.4 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(37.8 mg) as light yellow powdery solid.

MS (m/z): 276 (MH+)

Example 120

Cis-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride(Exemplary Compound No. 2-71)

(Step A) Synthesis of 5-bromo-4-methylisoquinoline (Intermediate 93)

4-Methylisoquinoline (0.1 ml, synthesized according to the methoddescribed in Tetrahedron. Lett. 34, 45, 7239 (1993)) was dissolved inconcentrated sulfuric acid (1 ml), then added with N-bromosuccinimide(125 mg) with ice cooling and stirred for 2 hours. The reaction mixturewas added with 28% aqueous ammonia (5 ml) and extracted twice withdichloromethane (10 ml for each time). The organic layer was dried overanhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=50:1) to obtain the title compound(108 mg).

(Step B) Synthesis ofcis-N-(tert-butoxycarbonyl)-N′-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 94)

According to the method of Example 15, Step A, the title compound wassynthesized from Intermediate 93. That is, under nitrogen atmosphere, asuspension of Intermediate 93 (602 mg),tris(dibenzylideneacetone)dipalladium(0) (124 mg),tri(tert-butyl)phosphine (0.5 ml, Kanto Chemicals),cis-N-(tert-butoxycarbonyl)-1,4-cyclohexanediamine (697 mg) and sodiumtert-butoxide (390 mg) in toluene was stirred with heating at 120° C.for 16.5 hours. The reaction mixture was cooled to room temperature andadded with ethyl acetate (10 ml), and the insoluble matters were removedby filtration through Celite. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound(45 mg).

(Step C) Synthesis ofcis-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 94 (35.8 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(30.3 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-1.90 (6H, m), 1.95-2.20 (2H, m),3.10-3.20 (4H, m), 3.72 (1H, br.s), 7.23 (1H, d, J=7.2 Hz), 7.70-7.80(2H, m), 8.20-8.50 (4H, m), 9.56 (1H, s)

MS (m/z): 256 (MH+)

Example 121

Trans-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride(Exemplary Compound No. 2-72)

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-N′-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 95)

According to the method of Example 15, Step A, the title compound wassynthesized from Intermediate 93. That is, under nitrogen atmosphere, asuspension of Intermediate 93 (1.13 g),tris(dibenzylideneacetone)dipalladium(0) (0.71 g),tri(tert-butyl)phosphine (0.5 ml),trans-N-(tert-butoxycarbonyl)-1,4-cyclohexanediamine (1.04 g) and sodiumtert-butoxide (0.73 g) in toluene was stirred with heating at 120° C.for 1 hour. The reaction mixture was cooled to room temperature andadded with ethyl acetate (50 ml), and the insoluble matters were removedby filtration through Celite. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound(456 mg).

(Step B) Synthesis oftrans-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 95 (389 mg) and 10%hydrogen chloride/methanol solution (10 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (2 ml)and diethyl ether (6 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(355 mg) as light yellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.70 (4H, m), 1.95-2.25 (4H, m),2.87-3.15 (4H, m), 3.35-3.55 (1H, m), 7.32 (1H, d, J=6.9 Hz), 7.65-7.80(2H, m), 8.20-8.40 (4H, m), 9.53 (1H, s)

MS (m/z): 256 (MH+)

Example 122

4-(4-Methoxy-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-37)

(Step A) Synthesis of4-(4-methoxy-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)-piperidine(Intermediate 96)

A suspension of Intermediate 71 (600 mg) and copper(I) iodide (141 mg,Kanto Chemicals) in methanol (5.5 ml) and pyridine (5.5 ml) was addedwith sodium methoxide (28% methanol solution, 1.7 ml, Wako Pure ChemicalIndustries) and stirred with heating at 65° C. for 24 hours. Thereaction mixture was cooled to room temperature, then added with water(30 ml) and extracted three times with ethyl acetate (20 ml for eachtime). The combined organic layer was washed twice with saturated brine(30 ml for each time) and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:2) to obtain the title compound (364 mg).

(Step B) Synthesis of 4-(4-methoxy-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 96 (358 mg) and 10% hydrogenchloride/methanol solution (10 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (336 mg) as lightyellow powdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.67-1.81 (2H, m), 2.16-2.25 (2H, m),2.97-3.14 (2H, m), 3.22-3.36 (2H, m), 3.75-3.85 (1H, m), 4.14 (3H, s),6.99 (1H, br.s), 7.16 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=8.1 Hz), 7.71(1H, t, J=8.1 Hz), 8.10 (1H, s), 9.13 (2H, br.s), 9.22 (1H, s)

MS (m/z): 258 (MH+)

Example 123

N-(4-Methoxy-5-isoquinolyl)-1,4-cyclohexanediamine hydrochloride

(Step A) Synthesis ofN-(tert-butoxycarbonyl)-N′-(4-methoxy-5-isoquinolyl)-1,4-cyclohexanediamine(Intermediate 97)

According to the method of Example 122, Step A, the title compound (392mg) was obtained from Intermediate 76 (621 mg), copper(I) iodide (141mg), methanol (5.5 ml), pyridine (5.5 ml) and sodium methoxide (28%methanol solution, 1.7 ml).

(Step B) Synthesis of N-(4-methoxy-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 97 (372 mg) and 10% hydrogenchloride/methanol solution (10 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (2 ml) and diethyl ether(6 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (348 mg) as lightyellow powdery solid.

MS (m/z): 272 (MH+)

Example 124

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(4-methanesulfonyl)phenylpropyl]-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-50)

(Step A) Synthesis of 3-(4-methanesulfonyl)phenyl-2-propyn-1-ol(Intermediate 98)

A solution of dichlorobis(benzonitrile)palladium(II) (230 mg, Aldrich),copper(I) iodide (76 mg), tri(tert-butyl)phosphine (299 μl),N,N-diisopropylamine (3.4 ml, Tokyo Kasei Kogyo),4-bromophenylmethylsulfone (4.7 g, Lancaster) and 2-propyn-1-ol (1.4 ml,Tokyo Kasei Kogyo) in 1,4-dioxane (25 ml) was stirred at roomtemperature for 12 hours. The reaction mixture was added with ethylacetate (50 ml), and the deposited precipitates were removed byfiltration through Celite. The solvent was evaporated under reducedpressure, and the residue was added with ethyl acetate (40 ml) andwashed successively with water (30 ml) and saturated brine (30 ml). Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtainthe title compound (1.52 g).

(Step B) Synthesis of 3-(4-methanesulfonyl)phenyl-1-propanol(Intermediate 99)

A solution of Intermediate 98 (1.26 g) in methanol (16 ml) wasvigorously stirred at room temperature in the presence of 10% palladiumcarbon catalyst (63 mg, Wako Pure Chemical Industries) under hydrogenatmosphere of ordinary pressure. The reaction mixture was filteredthrough Celite, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to obtain the title compound (1.13 g).

(Step C) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(4-methanesulfonyl)phenylpropyl]-1,3-propylenediamine(Intermediate 100)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (449 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 99 (429 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step D) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(4-methanesulfonyl)-phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 100 (281 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (230 mg) as whitepowdery solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.71-1.92 (4H, m), 2.54-2.60 (2H, m),2.70-2.80 (2H, m), 3.27-3.33 (2H, m), 3.39-3.46 (2H, m), 7.38 (2H, d,J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz), 7.99 (1H, t, J=7.8 Hz), 8.13 (3H,br.s), 8.50 (1H, d, J=7.8 Hz), 8.62 (1H, d, J=6.6 Hz), 8.67 (1H, d,J=8.1 Hz), 8.79 (1H, d, J=6.6 Hz), 9.84 (1H, s)

MS (m/z): 462 (MH+)

Example 125

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(3-methanesulfonyl)phenylpropyl]-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-49)

(Step A) Synthesis of 3-bromophenylmethylsulfone (Intermediate 101)

Trifluoroacetic acid (15 ml) was added with 3-bromothioanisole (5.17 g,Fluorochem) and added dropwise with 30% aqueous hydrogen peroxide (10ml, Wako Pure Chemical Industries) at 0° C. The reaction mixture wasstirred at room temperature for 3 hours, then cooled to 0° C. andneutralized with 5 N aqueous sodium hydroxide. The reaction mixture wasextracted twice with ethyl acetate (50 ml for each), and the combinedorganic layer was washed twice with saturated brine (100 ml for eachtime). The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue wasrecrystallized (n-hexane/acetone) to obtain the title compound (5.40 g)as white needle-like crystals.

(Step B) Synthesis of 3-(3-methanesulfonyl)phenyl-2-propyn-1-ol(Intermediate 102)

According to the method of Example 124, Step A, the title compound (1.33g) was obtained from Intermediate 101 (4.7 g),dichlorobis(benzonitrile)palladium(II) (230 mg, Aldrich), copper(I)iodide (76 mg), tri(tert-butyl)phosphine (299 μl), N,N-diisopropylamine(3.4 ml) and 2-propyn-1-ol (1.4 ml).

(Step C) Synthesis of 3-(3-methanesulfonyl)phenyl-1-propanol(Intermediate 103)

According to the method of Example 124, Step B, the title compound (1.19g) was obtained from Intermediate 102 (1.26 g).

(Step D) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(3-methanesulfonyl)phenylpropyl]-1,3-propylenediamine (Intermediate 104)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (462 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 103 (429 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step E) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(3-methanesulfonyl)-phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 104 (281 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (203 mg) as whitepowdery solid.

MS (m/z): 462 (MH+)

Example 126

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(2-methanesulfonyl)phenylpropyl]-1,3-propylenediaminehydrochloride (Exemplary Compound No. 3-48)

(Step A) Synthesis of 2-bromophenylmethylsulfone (Intermediate 105)

According to the method of Example 125, Step A, the title compound (5.22g) was obtained from 2-bromothioanisole (5.17 g, Tokyo Kasei Kogyo) aswhite needle-like crystals.

(Step B) Synthesis of 3-(3-methanesulfonyl)phenyl-2-propyn-1-ol(Intermediate 106)

According to the method of Example 124, Step A, the title compound (1.01g) was obtained from Intermediate 105 (4.7 g),dichlorobis(benzonitrile)palladium(II) (230 mg), copper(I) iodide (76mg), tri(tert-butyl)phosphine (299 μl), N,N-diisopropylamine (3.4 ml)and 2-propyn-1-ol (1.4 ml).

(Step C) Synthesis of 3-(2-methanesulfonyl)phenyl-1-propanol(Intermediate 107)

According to the method of Example 124, Step B, the title compound (580mg) was obtained from Intermediate 106 (630 mg).

(Step D) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(2-methanesulfonyl)phenylpropyl]-1,3-propylenediamine(Intermediate 108)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (440 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 107 (429 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step E) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(2-methanesulfonyl)-phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 108 (281 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (210 mg) as whitepowdery solid.

MS (m/z): 462 (MH+)

Example 127

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(4-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

(Step A) Synthesis of 3-(4-methoxycarbonyl)phenyl-2-propyn-1-ol(Intermediate 109)

According to the method of Example 124, Step A, the title compound (607mg) was obtained from methyl 4-bromobenzoate (1.72 g, Tokyo KaseiKogyo), dichlorobis(benzonitrile)palladium(II) (92 mg), copper(I) iodide(31 mg), tri(tert-butyl)phosphine (117 μl), N,N-diisopropylamine (1.35ml) and 2-propyn-1-ol (559 μl).

(Step B) Synthesis of 3-(4-methoxycarbonyl)phenyl-1-propanol(Intermediate 110)

According to the method of Example 124, Step B, the title compound (545mg) was obtained from Intermediate 109 (600 mg).

(Step C) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(4-methoxycarbonyl)phenylpropyl]-1,3-propylenediamine(Intermediate 111)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (433 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 110 (389 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step D) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(4-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

Intermediate 111 (271 mg) was added with concentrated hydrochloric acid(5 ml) and stirred with heating at 50° C. for 24 hours. The reactionmixture was cooled to room temperature, and then the solvent wasevaporated under reduced pressure. The residue was added with methanol(1 ml) and diethyl ether (3 ml). The deposited precipitates werecollected by filtration and washed with diethyl ether to obtain thetitle compound (194 mg) as white powdery solid.

MS (m/z): 428 (MH+)

Example 128

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(3-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

(Step A) Synthesis of 3-(3-methoxycarbonyl)phenyl-2-propyn-1-ol(Intermediate 112)

According to the method of Example 124, Step A, the title compound (610mg) was obtained from methyl 3-bromobenzoate (1.72 g, Tokyo KaseiKogyo), dichlorobis(benzonitrile)palladium(II) (92 mg), copper(I) iodide(31 mg), tri(tert-butyl)phosphine (117 μl), N,N-diisopropylamine (1.35ml) and 2-propyn-1-ol (559 μl).

(Step B) Synthesis of 3-(3-methoxycarbonyl)phenyl-1-propanol(Intermediate 113)

According to the method of Example 124, Step B, the title compound (550mg) was obtained from Intermediate 112 (600 mg).

(Step C) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(3-methoxycarbonyl)phenylpropyl]-1,3-propylenediamine(Intermediate 114)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (420 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 113 (389 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step D) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(3-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 127, Step D, the title compound (201mg) was obtained from Intermediate 114 (271 mg) as white powdery solid.

MS (m/z): 428 (MH+)

Example 129

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(2-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

(Step A) Synthesis of 3-(2-methoxycarbonyl)phenyl-2-propyn-1-ol(Intermediate 115)

According to the method of Example 124, Step A, the title compound (600mg) was obtained from methyl 2-bromobenzoate (1.72 g, Tokyo KaseiKogyo), dichlorobis(benzonitrile)palladium(II) (92 mg), copper(I) iodide(31 mg), tri(tert-butyl)phosphine (117 μl), N,N-diisopropylamine (1.35ml) and 2-propyn-1-ol (559 μl).

(Step B) Synthesis of 3-(2-methoxycarbonyl)phenyl-1-propanol(Intermediate 116)

According to the method of Example 124, Step B, the title compound (529mg) was obtained from Intermediate 115 (600 mg).

(Step C) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-N′-[3-(2-methoxycarbonyl)phenylpropyl]-1,3-propylenediamine(Intermediate 117)

According to the method of Example 1, Step B with the modifications thatthe reaction was carried out for 24 hours, and the compound was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1), thetitle compound (423 mg) was obtained from Intermediate 1 (365 mg),tri(n-butyl)phosphine (747 μl), Intermediate 116 (389 mg) and1,1′-azobis(N,N-dimethylformamide) (517 mg).

(Step D) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-N-[3-(2-carboxy)phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 127, Step D, the title compound (211mg) was obtained from Intermediate 117 (271 mg) as white powdery solid.

MS (m/z): 428 (MH+)

Example 130

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(4-methoxycarbonyl)phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 111 (271 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (199 mg) as whitepowdery solid.

MS (m/z): 442 (MH+)

Example 131

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(3-methoxycarbonyl)phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 114 (271 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (180 mg) as whitepowdery solid.

MS (m/z): 442 (MH+)

Example 132

N-[(5-Isoquinolyl)sulfonyl]-N-[3-(2-methoxycarbonyl)phenylpropyl]-1,3-propylenediaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 2 hours) by using Intermediate 117 (271 mg) and 10% hydrogenchloride/methanol solution (5 ml). The reaction mixture was cooled toroom temperature, and then the solvent was evaporated under reducedpressure. The residue was added with methanol (1 ml) and diethyl ether(3 ml). The deposited precipitates were collected by filtration andwashed with diethyl ether to obtain the title compound (189 mg) as whitepowdery solid.

MS (m/z): 442 (MH+)

Example 133

Trans-4-[(4-bromo-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

(Step A) Synthesis of cis-4-methoxybenzoic acid4-(tert-butoxycarbonylamino)cyclohexyl ester (Intermediate 118)

A solution of Intermediate 35 (21.06 g),1,1′-azobis(N,N-dimethylformamide) (64.11 g) and p-anisic acid (23.03 g,Tokyo Kasei Kogyo) in tetrahydrofuran (400 ml) was added withtri(n-butyl)phosphine (35.6 ml) at room temperature and stirred at 50°C. for 2.5 hours. The reaction mixture was cooled to room temperature,then added with ethyl acetate (200 ml) and successively washed withsaturated aqueous sodium hydrogencarbonate twice (200 ml each) and 0.1 Naqueous sodium hydroxide (50 ml), and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=5:1) to obtain the title compound (32.92 g).

(Step B) Synthesis of cis-4-(tert-butoxycarbonylamino)cyclohexanol(Intermediate 119)

A solution of Intermediate 118 (32.92 g) in methanol (400 ml) was addedwith 3 N aqueous sodium hydroxide (163 ml) at room temperature andstirred at 50° C. for 1.5 hours. The reaction mixture was cooled to roomtemperature, then added with ethyl acetate (400 ml) and washed 4 timeswith 0.5 N aqueous sodium hydroxide (50 ml each) and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound(7.94 g).

(Step C) Synthesis of 4-bromo-5-hydroxyisoquinoline (Intermediate 120)

A solution of 4-bromo-5-aminoisoquinoline (762 mg) obtained in ReferenceExample 1 in concentrated sulfuric acid (5 ml) was added with sodiumnitrite (235 mg) with ice cooling and stirring and stirred for 1.5hours. The reaction mixture was added with water (5 ml) and then stirredat 130° C. for 16 hours. The reaction mixture was neutralized with 28%aqueous ammonia solution, and the precipitates were collected byfiltration. The obtained solid was purified by silica gel columnchromatography (chloroform:methanol=40:1) to obtain the title compound(172 mg).

(Step D) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-bromo-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 121)

According to the method of Example 10, Step A except that the reactionwas performed for 27 hours, and the purification of the compound wasperformed by using silica gel column chromatography (n-hexane:ethylacetate=2:1), the title compound (166 mg) was obtained from Intermediate120 (160 mg), Intermediate 119 (466 mg),1,1′-azobis(N,N-dimethylformamide) (370 mg) and tri(n-butyl)phosphine(531 μl).

(Step E) Synthesis oftrans-4-[(4-bromo-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 121 (49.4 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(44.3 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.45-1.76 (4H, m), 1.99-2.13 (2H, m),2.18-2.31 (2H, m), 3.06-3.21 (1H, m), 4.51-4.67 (1H, m), 7.58 (1H, d,J=7.2 Hz), 7.70 (1H, t, J=8.1 Hz), 7.79 (1H, d, J=8.1 Hz), 8.10-8.35(3H, m), 8.65 (1H, s), 9.29 (1H, s)

MS (m/z): 321 (MH+)

Example 134

Trans-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-cyano-5-isoquinolyl)-oxy]cyclohexylamine(Intermediate 122)

A suspension of Intermediate 121 (113.7 mg), zinc cyanide (19.4 mg, WakoPure Chemical Industries), tris(dibenzylideneacetone)dipalladium(0)(24.0 mg) and 1,1′-bis(diphenylphosphino)ferrocene (35.3 mg, Tokyo KaseiKogyo) in DMF (2 ml) was stirred at 120° C. for 19 hours. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to obtain the title compound (34.9 mg).

(Step B) Synthesis oftrans-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 122 (34.9 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(22.4 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.47-1.74 (4H, m), 2.02-2.16 (2H, m),2.20-2.33 (2H, m), 3.01-3.21 (1H, m), 4.58-4.75 (1H, m), 7.64 (1H, d,J=7.2 Hz), 7.77 (1H, t, J=7.8 Hz), 7.84 (1H, d, J=8.1 Hz), 8.02-8.35(3H, m), 8.95 (1H, s), 9.53 (1H, s)

MS (m/z): 268 (MH+)

Example 135

Trans-4-[(5-isoquinolyl)oxy]cyclohexylamine hydrochloride (ExemplaryCompound No. 1-4)

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(5-isoquinolyl)oxy]-cyclohexylamine(Intermediate 123)

According to the method of Example 10, Step A except that the reactionwas performed for 21 hours, and the purification of the compound wasperformed by using silica gel column chromatography (n-hexane:ethylacetate=2:1), the title compound (64 mg) was obtained from5-hydroxyisoquinoline (108 mg), Intermediate 119 (484 mg),1,1′-azobis(N,N-dimethylformamide) (381 mg) and tri(n-butyl)phosphine(552 μl).

(Step B) Synthesis of trans-4-(5-isoquinolyloxy)cyclohexylaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 123 (59.6 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(52.8 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.50-1.74 (4H, m), 2.09 (2H, brs), 2.25 (2H,brs), 3.08-3.21 (1H, m), 4.62-4.72 (1H, m), 7.77 (1H, d, J=7.8 Hz), 7.89(1H, t, J=7.8 Hz), 8.02 (1H, d, J=8.1 Hz), 8.25-8.37 (3H, m), 8.40 (1H,d, J=6.3 Hz), 8.62 (1H, d, J=6.3 Hz), 9.81 (1H, s)

MS (m/z): 243 (MH+)

Example 136

Trans-4-[(4-vinyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-vinyl-5-isoquinolyl)-oxy]cyclohexylamine(Intermediate 124)

A solution of Intermediate 121 (500 mg), tri(n-butyl)vinyltin (518 μl,Tokyo Kasei Kogyo), tetrakis(triphenylphosphine)palladium(0) (28.1 mg)and 2,6-di-tert-butyl-p-cresol (3.2 mg, Tokyo Kasei Kogyo) in toluene(10 ml) was stirred at 110° C. for 3 hours. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=2:1) to obtain the titlecompound (409.5 mg).

(Step B) Synthesis oftrans-4-[(4-vinyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 124 (83.9 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(63.3 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.47-1.73 (4H, m), 2.01-2.12 (2H, m),2.18-2.27 (2H, m), 3.05-3.22 (1H, m), 4.57-4.68 (1H, m), 5.47 (1H, dd,J=1.5 Hz, 10.8 Hz), 5.67 (1H, dd, J=1.2 Hz, 11.1 Hz), 7.66-7.77 (2H, m),7.84 (1H, t, J=8.1 Hz), 7.98 (1H, d, J=7.2 Hz), 8.22-8.32 (3H, m), 8.46(1H, s), 9.63 (1H, s)

MS (m/z): 269 (MH+)

Example 137

Trans-4-[(4-amino-5-isoquinolyl)oxy]cyclohexylamine hydrochloride(Exemplary Compound No. 1-28)

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-amino-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 125)

A suspension of Intermediate 121 (100 mg),tris(dibenzylideneacetone)dipalladium(0) (22.1 mg),2-(di-tert-butylphosphino)biphenyl (33.9 mg) and sodium tert-butoxide(35.3 mg) in 0.5 N ammonia/dioxane solution (2 ml) was stirred at 70° C.for 22 hours. The reaction mixture was filtered through a Celite layer,and the solvent was evaporated under reduced pressure. Then, the residuewas purified by silica gel column chromatography(chloroform:methanol=9:1) to obtain the title compound (36.1 mg).

(Step B) Synthesis oftrans-4-[(4-amino-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 8 hours) by using Intermediate 125 (36.1 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(13.3 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.46-1.80 (4H, m), 2.01-2.12 (2H, m),2.18-2.31 (2H, m), 3.07-3.17 (1H, m), 3.18-3.75 (1.5H, m), 4.60-4.70(1H, m), 7.12 (1H, brs), 7.60 (1H, d, J=7.2 Hz), 7.71-7.80 (3H, m),8.10-8.30 (3H, m), 8.74 (1H, s)

MS (m/z): 258 (MH+)

Example 138

Trans-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 126)

A solution of Intermediate 124 (90.5 mg) in methanol (5 ml) was addedwith platinum oxide (13 mg, Wako Pure Chemical Industries) and stirredfor 15 hours under hydrogen atmosphere. The reaction mixture wasfiltered through a Celite layer, and the solvent was evaporated underreduced pressure. Then, the residue was purified by silica gel columnchromatography (chloroform:methanol=20:1) to obtain the title compound(41.1 mg).

(Step B) Synthesis oftrans-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 126 (41.1 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (0.5 ml)and diethyl ether (1.5 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(32.7 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.29 (3H, t, J=7.5 Hz), 1.53-1.73 (4H, m),2.08 (2H, brs), 2.31 (2H, brs), 3.05-3.19 (1H, m), 3.32 (2H, m),4.63-4.73 (1H, m), 7.78 (1H, d, J=8.1 Hz), 7.87 (1H, t, J=8.1 Hz), 8.01(1H, d, J=8.1 Hz), 8.23-8.38 (3H, m), 8.39 (1H, s), 9.64 (1H, s)

MS (m/z): 271 (MH+)

Example 139

4-[(4-Methyl-5-isoquinolyl)oxy]piperidine hydrochloride (ExemplaryCompound No. 1-19)

(Step A) Synthesis of 4-methyl-5-hydroxyisoquinoline (Intermediate 127)

A solution of 4-methyl-5-aminoisoquinoline (869 mg) in concentratedsulfuric acid (8 ml) was added with sodium nitrite (379 mg) with icecooling and stirring and stirred for 0.5 hours. The reaction mixture wasadded with water (12 ml) and then stirred at 130° C. for 16 hours. Thereaction mixture was neutralized with 28% aqueous ammonia solution andextracted with ethyl acetate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=30:1) to obtain the title compound(559 mg).

(Step B) Synthesis of4-(4-methyl-5-isoquinolyl)oxy-1-(tert-butoxycarbonyl)piperidine(Intermediate 128)

According to the method of Example 10, Step A except that the reactionwas performed for 21 hours, and the purification of the compound wasperformed by using silica gel column chromatography (n-hexane:ethylacetate=2:1), the title compound (686 mg) was obtained from Intermediate127 (530 mg), tert-butyl 4-hydroxy-1-piperidine-carboxylate (2.01 g),1,1′-azobis(N,N-dimethylformamide) (1.72 g) and tri(n-butyl)phosphine(2.46 ml).

(Step C) Synthesis of 4-[(4-methyl-5-isoquinolyl)oxy]piperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 128 (604 mg) and 10%hydrogen chloride/methanol solution (20 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (5 ml)and diethyl ether (15 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(513 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.95-2.13 (2H, m), 2.20-2.33 (2H, m), 2.91(3H, s), 3.05-3.35 (4H, m), 4.92-5.05 (1H, m), 7.65 (1H, d, J=7.5 Hz),7.84 (1H, t, J=8.1 Hz), 7.97 (1H, d, J=7.5 Hz), 8.41 (1H, s), 8.85-9.15(0.5H, m), 9.56 (1H, s)

MS (m/z): 243 (MH+)

Example 140

Trans-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride(Exemplary Compound No. 1-21)

(Step A) Synthesis oftrans-N-(tert-butoxycarbonyl)-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 129)

According to the method of Example 10, Step A except that the reactionwas performed for 18 hours, and the purification of the compound wasperformed by using silica gel column chromatography (n-hexane:ethylacetate=2:1), the title compound (194 mg) was obtained from Intermediate127 (473 mg), Intermediate 119 (1918 mg),1,1′-azobis(N,N-dimethylformamide) (1534 mg) and tri(n-butyl)phosphine(2.2 ml).

(Step B) Synthesis oftrans-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine hydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 129 (194 mg) and 10%hydrogen chloride/methanol solution (3.5 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(172 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.50-1.74 (4H, m), 2.08 (2H, brs), 2.27 (2H,brs), 2.88 (3H, s), 3.07-3.17 (1H, m), 4.57-4.68 (1H, m), 7.76 (1H, d,J=7.5 Hz), 7.86 (1H, t, J=7.8 Hz), 8.00 (1H, d, J=8.1 Hz), 8.27-8.44(4H, m), 9.65 (1H, s)

MS (m/z): 257 (MH+)

Example 141

Cis-4-[(1-amino-5-isoquinolyl)oxy]cyclohexylamine hydrochloride(Exemplary Compound No. 1-13)

(Step A) Synthesis ofcis-N-(tert-butoxycarbonyl)-4-[(1-chloro-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 130)

According to the method of Example 10, Step A except that the reactionwas performed for 18 hours, and the purification of the compound wasperformed by using silica gel column chromatography (n-hexane:ethylacetate=2:1), the title compound (1.93 g) was obtained from1-chloro-5-hydroxyisoquinoline (2.06 g), Intermediate 35 (7.41 g),1,1′-azobis(N,N-dimethylformamide) (5.93 g) and tri(n-butyl)phosphine(8.50 ml).

(Step B) Synthesis ofcis-N-(tert-butoxycarbonyl)-4-[(1-amino-5-isoquinolyl)oxy]cyclohexylamine(Intermediate 131)

A solution of Intermediate 130 (500 mg) in dioxane (2.5 ml) was addedwith 28% aqueous ammonia solution (2.5 ml) and stirred at 150° C. for 20hours in a sealed tube. The reaction mixture was cooled to roomtemperature, and then the solvent was evaporated under reduced pressure.The residue was added with dioxane (6 ml), 2 N aqueous sodium hydroxide(2 ml) and di-t-butyl dicarbonate (655 mg) and stirred at roomtemperature for 1 hour. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate:methanol=30:1) to obtain the titlecompound (95.0 mg).

(Step C) Synthesis of cis-4-[(1-amino-5-isoquinolyl)oxy]cyclohexylaminehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 131 (76 mg) and 10%hydrogen chloride/methanol solution (2 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(52 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.64-1.90 (6H, m), 1.97-2.11 (2H, m), 3.15(1H, brs), 4.92 (1H, brs), 7.48 (1H, d, J=7.2 Hz) 7.56 (1H, d, J=8.1Hz), 7.65-7.73 (2H, m), 8.12 (1H, d, J=8.4 Hz), 8.20 (3H, brs), 9.14(1.5H, brs), 13.56 (0.5H, brs)

MS (m/z): 258 (MH+)

Example 142

4-(1-Amino-5-isoquinolyl)aminopiperidine hydrochloride (ExemplaryCompound No. 2-12)

(Step A) Synthesis of4-[1-(4-methoxybenzyl)amino-5-isoquinolyl]amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 132)

A suspension of Intermediate 84 (235 mg), 4-methoxybenzylamine (110 μl),tris(dibenzylideneacetone)dipalladium(0) (30.4 mg),2-(di-tert-butylphosphino)biphenyl (41.0 mg) and sodium tert-butoxide(93.6 mg) in toluene (4.5 ml) was stirred at 70° C. for 1 hour. Thereaction mixture was filtered through a Celite layer, and the solventwas evaporated under reduced pressure. Then, the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtainthe title compound (270 mg).

(Step B) Synthesis of4-(1-amino-5-isoquinolyl)amino-1-(tert-butoxycarbonyl)piperidine(Intermediate 133)

A solution of Intermediate 132 (270 mg) in 95% trifluoroacetic acid (5ml) was stirred at 50° C. for 16 hours, and the solvent was evaporatedunder reduced pressure. The residue was added with dioxane (3 ml), 2 Naqueous sodium hydroxide (1 ml) and 2 di-t-butyl dicarbonate (393 mg)and stirred at room temperature for 1 hour. The solvent was evaporatedunder reduced pressure, and then the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate:isopropylamine=5:5:1) toobtain the title compound (199 mg).

(Step C) Synthesis of 4-(1-amino-5-isoquinolyl)aminopiperidine

According to the method of Example 1, Step C, deprotection was performed(room temperature, 2 hours) by using Intermediate 133 (199 mg) and 10%hydrogen chloride/methanol solution (3 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(101 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.70-1.85 (2H, m), 2.07-2.11 (2H, m),2.96-3.08 (2H, m), 3.30-3.40 (2H, m), 3.70-3.80 (1H, m), 6.36 (1H, d,J=7.2 Hz) 7.11 (1H, d, J=8.3 Hz), 7.54 (1H, t, J=8.1 Hz), 7.58-7.64 (2H,m), 7.72 (1H, d, J=8.3 Hz), 8.91 (2H, brs), 9.05 (2H, brs)

MS (m/z): 243 (MH+)

Example 143

4-(4-Cyano-5-isoquinolyl)aminopiperidine hydrochloride

(Step A) Synthesis of4-(4-bromo-5-isoquinolyl)oxy-1-(tert-butoxycarbonyl)piperidine(Intermediate 134)

According to the method of Example 10, Step A (room temperature, 72hours) except that the purification of the compound was performed byusing silica gel column chromatography (n-hexane:ethyl acetate=3:1), thetitle compound (175 mg) was obtained from Intermediate 120 (162 mg),tert-butyl 4-hydroxy-1-piperidinecarboxylate (437 mg),1,1′-azobis(N,N-dimethylformamide) (374 mg) and tri(n-butyl)phosphine(540 μl).

(Step B) Synthesis of4-(4-cyano-5-isoquinolyl)oxy-1-(tert-butoxycarbonyl)piperidine(Intermediate 135)

According to the method of Example 134, Step A (120° C., 12 hours)except that the purification of the compound was performed by silica gelcolumn chromatography (n-hexane:ethyl acetate=3:2), the title compound(596 mg) was obtained from Intermediate 134 (666 mg), zinc cyanide (138mg), tris(dibenzylideneacetone)dipalladium(0) (150 mg) and1,1′-bis(diphenylphosphino)ferrocene (186 mg).

(Step C) Synthesis of 4-(4-cyano-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 1, Step C, deprotection was performed(50° C., 30 minutes) by using Intermediate 135 (596 mg) and 10% hydrogenchloride/methanol solution (8 ml). The solvent was evaporated underreduced pressure, and the residue was added with methanol (10 ml) anddiethyl ether (30 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(286 mg).

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.14 (2H, m), 2.21-2.29 (2H, m), 3.10-3.21(2H, m), 3.33-3.45 (2H, m), 5.06-5.10 (1H, m), 7.60 (1H, d, J=8.0 Hz),7.79 (1H, t, J=8.0 Hz), 7.88 (1H, d, J=8.0 Hz), 8.90 (1H, br.s), 9.00(1H, s), 9.16 (1H, br.s), 9.56 (1H, s)

MS (m/z): 254 (MH+)

Example 144

1-(2-Hydroxyethyl)-4-(5-isoquinolyl)aminopiperidine hydrochloride

(Step A) Synthesis of1-[2-(tetrahydro-2H-pyranyloxy)ethyl]-4-(5-isoquinolyl)aminopiperidine(Intermediate 136)

A suspension of the compound of Example 20 (70 mg) and potassiumcarbonate (142 mg, Kokusan Chemical) in N,N-dimethylformamide (1.5 ml)was added with 2-(2-bromoethoxy)tetrahydro-2H-pyran (254 μl, Aldrich)and stirred at room temperature for 48 hours. The reaction mixture wasadded with acetone (10 ml), and insoluble matters were separated byfiltration. Then, the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=6:1) to obtain the title compound (40 mg).

(Step B)Trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexanehydrochloride

According to the method of Example 1, Step C, deprotection was performed(room temperature, 12 hours) by using Intermediate 136 (40 mg) and 10%hydrogen chloride/methanol solution (1.5 ml). The solvent was evaporatedunder reduced pressure, and the residue was added with methanol (1 ml)and diethyl ether (3 ml). The deposited precipitates were collected byfiltration and washed with diethyl ether to obtain the title compound(35 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.91-2.20 (4H, m), 3.10-3.99 (9H, m),7.23-7.27 (1H, m), 7.65-7.84 (2H, m), 8.59-8.65 (1H, m), 8.88-9.02 (1H,m), 9.73-9.76 (1H, m), 10.30-10.70 (1H, m)

MS (m/z): 272 (MH+)

Example 145

1-(3-Hydroxypropyl)-4-(5-isoquinolyl)aminopiperidine hydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran (Aldrich) and a deprotectionreaction were performed by using the compound of Example 20 to obtainthe title compound.

MS (m/z): 286 (MH+)

Example 146

1-(2-Hydroxyethyl)-4-(4-methyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 106 to obtain the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.87-2.28 (4H, m), 3.00-3.90 (12H, m), 5.80(1H, brs), 7.29-7.37 (1H, m), 7.72-7.80 (2H, m), 8.26-8.33 (1H, m),9.50-9.73 (1H, m), 10.47 (1H, brs)

MS (m/z): 286 (MH+)

Example 147

1-(3-Hydroxypropyl)-4-(4-methyl-5-isoquinolyl)aminopiperidinehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 106 to obtain the titlecompound.

MS (m/z): 300 (MH+)

Example 148

Trans-N-(5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 24 to obtain the titlecompound.

MS (m/z): 286 (MH+)

Example 149

Trans-N-(5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 24 to obtain the titlecompound.

MS (m/z): 300 (MH+)

Example 150

Trans-N-(4-methyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 121 to obtain the titlecompound.

MS (m/z): 300 (MH+)

Example 151

Trans-N-(4-methyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 121 to obtain the titlecompound.

MS (m/z): 314 (MH+)

Example 152

Cis-N-(5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 23 to obtain the titlecompound.

MS (m/z): 286 (MH+)

Example 153

Cis-N-(5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 23 to obtain the titlecompound.

MS (m/z): 299 (MH+)

Example 154

Cis-N-(4-methyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 120 to obtain the titlecompound.

MS (m/z): 299 (MH+)

Example 155

Cis-N-(4-methyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 120 to obtain the titlecompound.

MS (m/z): 314 (MH+)

Example 156

Trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexanehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 134 to obtain the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.57-1.71 (4H, m), 2.16-2.35 (4H, m),2.96-3.08 (2H, m), 3.09-3.23 (1H, m), 4.60-4.72 (1H, m), 6.72 (1H, brs),7.65 (1H, d, J=7.2 Hz), 7.70 (1H, t, J=7.5 Hz), 7.85 (1H, d, J=7.2 Hz),9.53 (1H, s)

MS (m/z): 312 (MH+)

Example 157

Trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexanehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 134 to obtain the titlecompound.

MS (m/z): 326 (MH+)

Example 158

1-(2-Hydroxyethyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidinehydrochloride

According to the method of Example 144, an alkylation reaction with2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 143 to obtain the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm): 2.10-2.45 (4H, m), 3.10-3.60 (4H, m),3.60-3.72 (2H, m), 3.75-3.83 (2H, m), 4.89-4.96 (1H, m), 7.59-7.65 (1H,m), 7.77-7.82 (1H, m), 7.87-7.90 (1H, m), 8.57 (1H, br.s), 9.02 (1H, s),9.57 (1H, s), 9.93 (1H, br.s), 10.29 (1H, br.s)

MS (m/z): 298 (MH+)

Example 159

1-(3-Hydroxypropyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidinehydrochloride

According to the method of Example 144, an alkylation reaction with2-(3-bromopropoxy)tetrahydro-2H-pyran and a deprotection reaction wereperformed by using the compound of Example 143 to obtain the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.80-2.00 (2H, m), 2.10-2.48 (4H, m),3.05-3.20 (2H, m), 3.20-3.75 (6H, m), 4.85-4.96 (1H, m), 7.59-7.63 (1H,m), 7.79 (1H, t, J=7.9 Hz), 7.88 (1H, d, J=8.1 Hz), 9.01 (1H, s), 9.55(1H, s), 10.23 (1H, br.s), 10.88 (1H, br.s)

MS (m/z): 312 (MH+)

Example 160

Trans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-4-cyclohexanediaminehydrochloride

(Step A) Synthesis of 1-hydroxy-4-bromo-5-nitroisoquinoline(Intermediate 137)

According to the method of Example 12, Step B, a hydrolysis reactionwith concentrated hydrochloric acid was performed by using a knowncompound, 1-chloro-4-bromo-5-nitroisoquinoline (Indian. J. Chem., 224,1967), to obtain the title compound.

(Step B) Synthesis of 1-hydroxy-4-bromo-5-aminoisoquinoline(Intermediate 138)

According to the method of Example 114, Step A, a reduction reactionwith tin(II) chloride dihydrate was performed by using Intermediate 137to obtain the title compound.

(Step C) Synthesis of 1-hydroxy-4-methyl-5-aminoisoquinoline(Intermediate 139)

According to the method of Example 106, Step A, a methylation reactionwith tetramethyltin was performed by using Intermediate 138 to obtainthe title compound.

(Step D) Synthesis oftrans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-N′-(tert-butoxycarbonyl)-1,4-cyclohexanediamine(Intermediate 140)

According to the method of Example 107, Step A, a reductive alkylationreaction with tert-butyl 4-oxo-1-aminocyclohexylcarboxylate wasperformed by using Intermediate 139, and fractionation recrystallizationwas performed from ethyl acetate to separate the cis-compound to obtainthe title compound.

(Step E) Synthesis oftrans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediaminehydrochloride

According to the method of Step A of this example, deprotection withconcentrated hydrochloric acid was performed by using Intermediate 140to obtain the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.39-1.56 (4H, m), 2.00-2.12 (2H, m), 2.51(3H, s), 2.94-3.04 (1H, m), 3.22-3.32 (1H, m), 6.80 (1H, s), 7.12 (1H,d, J=6.9 Hz), 7.31 (1H, t, J=7.8 Hz), 7.69 (1H, d, J=7.5 Hz), 8.18 (3H,brs), 11.10 (1H, brs)

MS (m/z): 272 (MH+)

Reference Example 1

4-Bromo-5-aminoisoquinoline

(Step A) Synthesis of 4-bromo-5-nitroisoquinoline

With vigorous stirring, concentrated sulfuric acid (36 ml) was addedwith 4-bromoisoquinoline (10.0 g, Tokyo Kasei Kogyo) to such an extentthat the temperature should not exceed 10° C. and stirred for a while toattain complete dissolution. Potassium nitrate (4.9 g, Kanto Chemicals)was dissolved in concentrated sulfuric acid (20 ml), added dropwise tothe aforementioned solution at a temperature below −5° C. and furtherstirred for 2 hours while maintaining that temperature. Disappearance of4-bromoisoquinoline was confirmed by thin layer chromatography(n-hexane:ethyl acetate=1:1), and then the reaction mixture was slowlypoured into cold aqueous ammonia (200 ml, Wako Pure Chemical Industries)with vigorous stirring. The reaction mixture was stirred for 15 minutesand then extracted three times with ethyl acetate (150 ml for eachtime), and the combined organic layer was washed successively with water(250 ml) and saturated brine (250 ml) and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was recrystallized with ethyl acetate to obtain the titlecompound (5.9 g) as thick yellow needle-like crystals.

(Step B) Synthesis of 4-bromo-5-aminoisoquinoline

4-Bromo-5-nitroisoquinoline (1.0 g) synthesized as described above andstannous chloride dihydrate (4.5 g, Wako Pure Chemical Industries) weresuspended in ethanol (30 ml), added with concentrated hydrochloric acid(2.3 ml) and stirred at 80° C. for 30 minutes and at room temperaturefor further 12 hours. The reaction mixture was adjusted to pH 12 withaddition of 2 N aqueous sodium hydroxide. The target compound wasextracted three times with ethyl acetate (100 ml for each time), and thecombined organic layer was washed with water (200 ml) and saturatedbrine (200 ml) and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and then the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtainthe title compound (493 mg) as yellow powdery crystals.

¹H-NMR(CDCl₃) δ (ppm): 5.23 (2H, br.s), 6.92 (1H, dd, J=1.6, 7.3 Hz),7.38 (2H, m), 8.50 (1H, s), 8.98 (1H, s)

Reference Example 2

Synthesis of N-[(5-isoquinolyl)sulfonyl]ethylenediamine (Intermediate49)

Isoquinoline-5-sulfonyl chloride hydrochloride (33 g, prepared accordingto the method described in Japanese Patent Unexamined Publication(Kokai) No. 57-200366) was added to dichloromethane (300 ml) and water(300 ml), added with sodium hydrogencarbonate with vigorous stirringuntil pH of the aqueous layer became 5 to 6. The reaction mixture wasfurther extracted three times with dichloromethane, and the organiclayer was dried over anhydrous magnesium sulfate. This solution wasadded dropwise to a solution of ethylenediamine (30 g) indichloromethane (600 ml) over 2 hours with ice cooling and stirred atroom temperature for 30 minutes. After completion of the reaction, thereaction mixture was added with diluted hydrochloric acid with vigorousstirring to adjust pH of the aqueous layer to about 8. The organic layerand the aqueous layer were separated, and then the aqueous layer wascollected and added with potassium carbonate to obtain a saturatedsolution, which was extracted with dichloromethane (600 ml). The organiclayer was dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure to obtain the title compound (22.9g).

Reference Example 3

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-propylenediamine(Intermediate 50)

According to the method of Reference Example 2, a reaction was performedby using isoquinoline-5-sulfonyl chloride hydrochloride (20 g) and1,3-propylenediamine (22.2 g) to obtain the title compound (16.3 g).

Reference Example 4

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,4-butylenediamine(Intermediate 51)

According to the method of Reference Example 2, a reaction was performedby using isoquinoline-5-sulfonyl chloride hydrochloride (18.8 g) and1,4-butylenediamine (25 g) to obtain the title compound (12.3 g).

Reference Example 5

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-cyclohexanediamine(Intermediate 52)

(Step A) Synthesis of 3-(N-tert-butoxycarbonylamino)cyclohexylamine(Intermediate 53)

3-Diaminocyclohexanediamine (25 g) was dissolved in chloroform (500 ml),added with di-t-butyl dicarbonate (23.9 g) with stirring and ice coolingand stirred at room temperature for 16 hours. The solvent of thereaction mixture was evaporated under reduced pressure, and the residuewas added with dichloromethane and saturated aqueous sodium carbonatefor extraction. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography(chloroform:methanol:triethylamine=100:10:1) to obtain the titlecompound (16 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-1,3-cyclohexanediamine(Intermediate 54)

Dichloromethane (80 ml) and water (80 ml) were added withisoquinoline-5-sulfonyl chloride hydrochloride (8 g) and added withsodium hydrogencarbonate with vigorous stirring until pH of the aqueouslayer became 5 to 6, and further, the reaction mixture was extractedthree times with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate. This solution was added dropwise to asolution containing Intermediate 53 (6.5 g) mentioned above andtriethylamine (4.3 ml) in dichloromethane (50 ml) with ice cooling andstirred at room temperature for 4 hours. The reaction mixture was washedsuccessively with water and saturated brine. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography (chloroform:methanol=40:1) to obtain the title compound(6 g).

(Step C) Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-cyclohexanediamine

Intermediate 54 (6 g) obtained above was added to a 10% hydrogenchloride solution in methanol (50 ml) and stirred under reflux byheating for 1.5 hours. The solvent was evaporated under reducedpressure, and the residue was dissolved in a mixed solvent ofdichloromethane and ethanol, added with saturated aqueous potassiumcarbonate and vigorously shaken. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to obtain the title compound (4.9 g).

Reference Example 6

Synthesis ofN-[(5-isoquinolyl)sulfonyl]-2,2-dimethyl-1,3-propylenediamine(Intermediate 55)

(Step A) Synthesis of3-(N-tert-butoxycarbonylamino)-2,2-dimethylpropylamine (Intermediate 56)

Water (340 ml) and t-butyl alcohol (200 ml) were added with2,2-dimethyl-1,3-propylenediamine (25 g), added successively with 4 Naqueous sodium hydroxide (20.5 ml) and a solution of di-t-butyldicarbonate (21.4 g) in t-butyl alcohol with ice cooling and stirred atroom temperature for 16 hours. The solvent (t-butyl alcohol) wasevaporated under reduced pressure, and the residue was extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine and dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography (ethyl acetate:methanol=10:1) to obtain the titlecompound (6 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-2,2-dimethyl-1,3-propylenediamine(Intermediate 57)

According to Reference Example 5, Step B, a reaction was performed byusing isoquinoline-5-sulfonyl chloride hydrochloride (7.8 g) andIntermediate 56 (5.97 g) to obtain the title compound (11.36 g).

(Step C) Synthesis ofN-[(5-isoquinolyl)sulfonyl]-2,2-dimethyl-1,3-propylenediamine

According to Reference Example 5, Step C, a reaction was performed byusing Intermediate 57 (11 g) and 10% hydrogen chloride in methanol (80ml) to obtain the title compound (7.58 g).

Reference Example 7

Synthesis of N-[(5-Isoquinolyl)sulfonyl]-1,4-xylylenediamine(Intermediate 58)

(Step A) Synthesis of 4-(N-tert-butoxycarbonylaminomethyl)benzylamine(Intermediate 59)

According to Reference Example 6, Step A, a reaction was performed byusing p-xylylenediamine (25 g) to obtain the title compound (9 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-1,4-xylylenediamine(Intermediate 60)

According to Reference Example 5, Step B, a reaction was performed byusing isoquinoline-5-sulfonyl chloride hydrochloride (10 g) andIntermediate 59 (8.96 g) to obtain the title compound (13.39 g).

(Step C) Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,4-xylylenediamine

According to Reference Example 5, Step C, a reaction was performed byusing Intermediate 60 (6 g) and 10% hydrogen chloride in methanol (20ml) to obtain the title compound (3.7 g).

Reference Example 8

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-xylylenediamine(Intermediate 61)

(Step A) Synthesis of 3-(N-tert-butoxycarbonylaminomethyl)benzylamine(Intermediate 62)

According to Reference Example 6, Step A, a reaction was performed byusing m-xylylenediamine (25 g) to obtain the title compound (8 g).

(Step B) Synthesis ofN-(tert-butoxycarbonyl)-N′-[(5-isoquinolyl)sulfonyl]-1,3-xylylenediamine(Intermediate 63)

According to Reference Example 5, Step B, a reaction was performed byusing isoquinoline-5-sulfonyl chloride hydrochloride (9 g) andIntermediate 62 (8 g) to obtain the title compound (11.3 g).

(Step C) Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-xylylenediamine

According to Reference Example 5, Step C, a reaction was performed byusing Intermediate 63 (5 g) and 10% hydrogen chloride in methanol (20ml) to obtain the title compound (3.1 g).

Reference Example 9

Synthesis of N-[(5-isoquinolyl)sulfonyl]ethylenediamine Carried by Crownvia Trityl Linker (Intermediate 64)

Hydroxyl groups of SynPhase Crown (I Series, 8.3 μmol/crown) having atrityl linker produced by Chiron Technologies (currently Mitocore) werechlorinated by allowing a mixed solvent of dichloromethane and acetylchloride to act on the crown for 18 hours, and washing the crown twicewith dichloromethane. Then, a solution of Intermediate 49 of ReferenceExample 2 and N-methylmorpholine in dimethylformamide was allowed to acton the obtained trityl chloride crown for 21 hours, and the obtainedcrown was washed with dimethylformamide, methanol and dichloromethanethree times for each to obtain the title compound.

Reference Example 10

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-propylenediamine Carried byCrown via Trityl Linker (Intermediate 65)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 50 of Reference Example 3 instead of Intermediate49 to obtain the title compound.

Reference Example 11

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,4-butylenediamine Carried byCrown via Trityl Linker (Intermediate 66)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 51 of Reference Example 4 instead of Intermediate49 to obtain the title compound.

Reference Example 12

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-cyclohexanediamine Carriedby Crown via Trityl Linker (Intermediate 67)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 52 of Reference Example 5 instead of Intermediate49 to obtain the title compound.

Reference Example 13

Synthesis ofN-[(5-isoquinolyl)sulfonyl]-2,2-dimethyl-1,3-propylenediamine Carried byCrown via Trityl Linker (Intermediate 68)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 55 of Reference Example 6 instead of Intermediate49 to obtain the title compound.

Reference Example 14

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,4-xylylenediamine Carried byCrown via Trityl Linker (Intermediate 69)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 58 of Reference Example 7 instead of Intermediate49 to obtain the title compound.

Reference Example 15

Synthesis of N-[(5-isoquinolyl)sulfonyl]-1,3-xylylenediamine Carried byCrown via Trityl Linker (Intermediate 70)

According to the method of Reference Example 9, a reaction was performedby using Intermediate 61 of Reference Example 8 instead of Intermediate49 to obtain the title compound.

Test Example 1

Action on Amount of Phosphorylated Myosin Regulatory Light Chain in theCells

A volume of 50 to 100 ml of peripheral blood collected from healthyvolunteers was centrifuged by using Mono-Poly separator solution(Dainippon Pharmaceutical) to prepare a neutrophil containing fraction.The neutrophils were washed with PBS(−) and resuspended in Hanks'Balanced Salt Solution (HBSS+, Gibco) to prepare a cell suspension(8×10⁶/ml). The cell suspension was diluted to 5×10⁶/ml, introduced intoEppendorf tubes in a volume of 0.4 ml each, then 0.1 ml each ofsolutions of a test compound at various concentrations were added to thesuspension and allowed to react at 25° C. for 5 minutes. After thereaction, 0.1 ml of trichloroacetic acid solution was added to eachreaction, the reaction mixture was gently shaken and centrifuged at12,000 rpm (4° C., 5 minutes), and the supernatant was removed.Subsequently, 3 μl of 1 M Tris solution was added to the residue, themixture was further mixed with 50 μl of extraction buffer (8 M urea,0.02% 2-mercaptoethanol, 0.002% bromophenol blue) and left stand at roomtemperature for 1 hour. Then, the reaction mixture was loaded on a spincolumn (0.45 μm, Millipore) to remove the insoluble solids and a samplebuffer for SDS polyacrylamide gel electrophoresis (25 mM, Tris-HCl pH6.8, 2.5% 2-mercaptoethanol, 2% sodium dodecylsulfate, 5% sucrose,0.002% bromophenol blue as final concentrations) was added, and 10 μl ofeach sample was subjected to electrophoresis.

The gel after the electrophoresis was blotted on a nitrocellulosemembrane (BioRad), blocked with 5% skim milk, and reacted successivelywith antibodies pLC1 (Sakurada K. et al, Am. J. Physiol., 274,C1563-C1572 (1998)), which specifically recognize the phosphorylatedmyosin regulatory light chain, and donkey anti-mouse IgG (Chemicon)conjugated with horseradish peroxidase (HRP-labeled). The band of thephosphorylated myosin regulatory light chain was detected on a film byusing ECL Plus Kit (Amersham Pharmacia Biotech). This band was subjectedto quantification using a densitometer. By using this value, theinhibitory ratio (%) for phosphorylation of the myosin regulatory lightchain was calculated by using the following equation.Phosphorylation inhibition ratio (%)=1−(Band intensity of phosphorylatedmyosin regulatory light chain with addition of the test compound/Bandintensity of phosphorylated myosin regulatory light chain withoutaddition of the test compound)×100

Further, the phosphorylation inhibition ratio was calculated withchanging the concentrations of the test compound, and a compoundconcentration providing an inhibition ratio of 50% was obtained as IC₅₀.

The results are shown in Table 5 mentioned below. It was revealed thatthe compounds of the present invention inhibited phosphorylation of themyosin regulatory light chain. TABLE 5 Inhibition of myosin regulatorylight chain phosphorylation Test compound (IC₅₀: μM) H-7 80.0 Example 10.8 Example 2 0.8 Example 4 30.0 Example 5 0.8 Example 6 20.0 Example 730.0 Example 8 0.3 Example 9 15.0 Example 10 10.0 Example 11 20 ≧ IC₅₀ >1  Example 12 20.0 Example 13 20.0 Example 14 40 ≧ IC₅₀ > 20 Example 1640 ≧ IC₅₀ > 20 Example 18 40 ≧ IC₅₀ > 20 Example 20 1.8 Example 23 20 ≧IC₅₀ > 1  Example 24 20 ≧ IC₅₀ > 1  Example 25 40 ≧ IC₅₀ > 20 Example 2640 ≧ IC₅₀ > 20 Example 27 20 ≧ IC₅₀ > 1  Example 30 40 ≧ IC₅₀ > 20Example 32 40 ≧ IC₅₀ > 20 Example 33 40 ≧ IC₅₀ > 20 Example 34 40 ≧IC₅₀ > 20 Example 38 40 ≧ IC₅₀ > 20 Example 39 40 ≧ IC₅₀ > 20 Example 4040 ≧ IC₅₀ > 20 Example 41 40 ≧ IC₅₀ > 20 Example 42 20 ≧ IC₅₀ > 1 Example 43 40 ≧ IC₅₀ > 20 Example 44 40 ≧ IC₅₀ > 20 Example 45 40 ≧IC₅₀ > 20 Example 48 40 ≧ IC₅₀ > 20 Example 51 40 ≧ IC₅₀ > 20 Example 5740 ≧ IC₅₀ > 20 Example 71 40 ≧ IC₅₀ > 20

In addition to the compounds mentioned in the table, each of thecompounds of Examples 21, 22, 29, 103, 104, 105, 106, 107, 112, 113,118, 120, 121, 124, 128, 130, 131, 133, 134, 135, 136, 137, 138, 139,140, 142, 143, 144, 145, 146, 156 and 160, which falls within thecompounds of the present invention, gave an IC₅₀ of 40 μM or less, andeach of the compounds of Examples 21, 29, 103, 104, 106, 107, 112, 113,118, 120, 121, 124, 128, 130, 131, 133, 134, 135, 136, 137, 138, 139,140, 142, 145, 146, 156 and 160 gave an IC₅₀ of 20 μM or less.

Test Example 2

Vasoconstriction Inhibitory Action

Rats (Wistar, 11-week old) were bleeded to death and laparotomized totake out the thoracic aorta. That aorta was cut into a ring of a lengthof about 3 mm in a conventional manner (Asano,T., et al., J. Pharmacol.Exp. Ther., 241, pp.1033-1040 (1987)) and hung in 10-ml organ bathfilled with Krebs-Hensright nutrient solution bubbled with a mixed gasof 95% O₂ and 5% CO₂. One end of the blood vessel was connected to anisometric transducer (FD Pickup TB-912T, Nihon Kohden) and applied with2.5 g of resting tension, and constriction and relaxation reactions ofthe aorta were recorded. The aorta was constricted with phenylephrine (1μM, Sigma) and then added with a test compound (1 μM), and thevasoconstriction inhibitory action thereof was observed. Thevasoconstriction inhibitory actions of the test compounds are shown inTable 6 mentioned below as the relaxation ratios, which are based on thevasoconstriction with phenylephrine immediately before the addition ofthe test compound taken as 100%.

H-7: 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (SeikagakuCorporation) TABLE 6 Vasoconstriction inhibitory action Test compound(1μM) (relaxation ratio) (%) Physiological saline 0 H-7 22.0 Example 173.8 Example 7 64.3 Example 20 82.8

In addition to the compounds shown in the table, each of the compoundsof Examples 2, 5, 8, 12, 13, 105, 106, 112, 113, 120, 121, 134, 136,139, 140 and 146, which falls within the compounds of the presentinvention, also gave significant vasoconstriction inhibitory action.

Thus, it was confirmed that the compounds of the present invention wereuseful as medicaments for prophylactic and/or therapeutic treatment ofdiseases relating to cell contraction.

Test Example 3

Respiratory Tract Constriction Suppression Action

Four-week old Hartley guinea pigs (male) were immunized byintraperitoneal administration of ovalbumin (Sigma, Grade V) in amountsof 1 mg for each animal on the day on which the experiment was started,3 mg for each animal after 2 days, and 10 mg for each animal after 4days.

Twelve to fourteen days after the final immunization, theovalbumin-immunized guinea pigs were anesthetized by intraperitonealadministration of about 40 mg/kg of pentobarbital (Somnopentyl), and thetracheas were taken out. Subsequently, a cannula (SP-110, Natsume) wasinserted into each trachea, and one end of the cannula was connected toan artificial respirator (Model-b83, Harvard). The aeration conditionswere set at 6 ml per kilogram and 60 times per 1 minute. Further, acannula for medicament administration (JMS wing needle 23G 3/4) wasinserted into a hind leg vein. Myoblock (Organon Technica) wasadministered in an amount of 0.5 mg/kg from the cannula inserted intothe hind leg vein to stop the spontaneous breathing, and after 2 or 3minutes, 0.3 mg/kg of ovalbumin was administered to induce constrictionof respiratory tract. The increase of airway resistance value 2 minutesafter the induction (measurement apparatuses: pressure transducerTR-603T, respiratory amplifier AR-601G, and recorder RTA-3100, NihonKohden Corp.) was confirmed to be above 80 cm H₂O or higher, and then, asolution of a test medicament was administered from the cannula insertedinto the hind leg vein, and the airway resistance value was continuouslymeasured for 15 minutes after the administration to determine theeffect.

As a result, each of the compounds of Examples 2, 11, 12, 20, 29, 106,118, 121, 133, 140, 144 and 146, which falls within the compounds of thepresent invention, significantly improved the constriction ofrespiratory tract. Therefore, it was confirmed that the compounds of thepresent invention were useful as medicaments for prophylactic and/ortherapeutic treatment of bronchial asthma and/or chronic obstructivepulmonary disease (COPD).

Test Example 4

Intraocular Pressure Reducing Action

A Japanese white rabbit having a body weight of about 2 kg was placed ina positioner and naturalized for one week before the experiment. Anophthalmologic local anesthesant (Benoxil) was administered to the lefteye, and then intraocular pressure was measured by using a tonometer(Classic 30, Solan). The initial value of the intraocular pressure wasmeasured, then 50 μl of a test compound (1% aqueous solution) wasdropped to the left eye, and after 2 hours, the intraocular pressure wasmeasured. The intraocular pressure reducing action of the test compoundsis shown in Table 7 mentioned below as ratios (%) of reduction ofintraocular pressure based on the initial value of the intraocularpressure. TABLE 7 Test compound Intraocular pressure reducing action(1%) (reduction ratio) (%) Physiological saline 0 Example 7 30.1 Example12 13.3 Example 20 35.7 Example 24 35.7 Example 27 12.5 Example 29 18.8Example 103 31.3 Example 104 18.8 Example 105 18.8 Example 106 31.3Example 112 25.0 Example 118 25.0 Example 121 31.3 Example 124 12.5

In addition to the compounds shown in the table, each of the compoundsof Examples 107, 113, 115, 120, 133, 134, 135, 136, 139, 140, 144, 145and 146, which falls within the compounds of the present invention, alsogave significant intraocular pressure reducing activity.

Thus, it was confirmed that the compounds of the present invention wereuseful as medicaments for prophylactic and/or therapeutic treatment of,in particular, glaucoma.

Test Example 5

Neutrophil Migration Inhibitory Action

Neutrophils were isolated from 50 to 100 ml of peripheral bloodcollected from healthy donors by the method described in Test Example 1to obtain a cell suspension (8×10⁶/ml). Subsequently, solutions of atest compound at various concentrations were introduced into wells of a96-well plate in a volume of 125 μl per well, the cell suspension of anequivalent volume was added to it and the plate was preincubated at roomtemperature for 5 minutes. During the preincubation, FMLP (1 μM, Sigma)solution was added to the lower chamber to set Boyden Chamber, thepreincubated cell suspension was added to the upper chamber in a volumeof 200 μl per well, and the cells were allowed to migrate at 37° C.under 5% carbon dioxide for 30 minutes. The filter after the migrationwas collected, and the non-migrated cells adhered to the surface thatfaced the upper chamber were carefully wiped off. Then, the migratedcells on the back surface were stained with DifQuick dye solution(International Reagents), washed with water and dried, and thenabsorbance was measured at 595 nm. The inhibition ratio againstmigration (%) of a test compound was calculated by using the followingequation:Migration inhibition ratio (%)=(1−Absorbance of the group with additionof test compound/Absorbance of the group without addition of testcompound)×100

Further, the migration inhibitory ratio was calculated with changing thetest compound concentration, and a compound concentration providing aninhibition ratio of 50% was obtained as IC₅₀. The results are shown inTable 8 mentioned below. The compounds of the present invention hadstronger activity than that of H-7 as being a prior art compound. TABLE8 H-7 > 40 μM Compounds for which 40 μM > IC₅₀ > 10 μM Example 16,Example 18, Example 21, Example 25, Example 26, Example 31, Example 35,Example 37, Example 38, Example 39, Example 46, Example 47, Example 48,Example 50, Example 51, Example 57, Example 59, Example 70, Example 71,Example 73, Example 79, Example 106, Example 118 Compounds for which 10μM ≧ IC₅₀ > 1 μM Example 2, Example 4, Example 6, Example 9, Example 10,Example 11, Example 12, Example 13, Example 14, Example 20, Example 23,Example 24, Example 30, Example 32, Example 33, Example 34, Example 40,Example 41, Example 42, Example 43, Example 44, Example 45, Example 103,Example 121 Compounds for which 1 μM ≧ IC₅₀ Example 1, Example 5,Example 8

In addition to the compounds mentioned above, each of the compounds ofExamples 27, 29, 104, 107, 112, 113, 118, 120, 128, 130, 131, 133, 134,135, 136, 137, 138, 139, 140, 145, 146, 156 and 160, which falls withinthe compounds of the present invention, gave an IC₅₀ of 40 μM or less,and each of the compounds of Examples 107, 120, 130, 133, 134, 135, 138,139, 140 and 156 gave an IC₅₀ of 10 μM or less.

Thus, it was confirmed that the compounds of the present invention wereuseful as medicaments for prophylactic and/or therapeutic treatment ofdiseases relating to cell migration.

Test Example 6

Respiratory Tract Inflammation Suppressing Action

According to the method described in Henderson, W. R., et al., Am. J.Respir. Cric. Care Med., 165(1), 108-116 (2002), suppressing action onbronchial inflammation was confirmed. BALB/c female mice (7-week old)were used for the test, each group consisting of 7 mice, and the controlgroup consisting of 11 or 12 mice. The mice were intraperitoneallyadministered with ovalbumin (OVA, 100 ng, Sigma) and 1 mg of aluminumhydroxide for initial immunization, and after 2 weeks, they aresubcutaneously administered with 10 ng of OVA as additionalimmunization. After further 1 week, a test compound was dissolved inwater containing 0.5% carboxymethylcellulose and orally administered (30mg/kg) to the test animals once a day for 5 days. The control group wassimilarly given only with water containing 0.5% carboxymethylcellulose.After 1 hour, the mice were orally inhaled with 2% OVA for 10 minutes toinduce a respiratory tract inflammation. Further, the control group, inwhich the mice were not given with the test compound, was divided into apositive control group (n=7), in which the mice were inhaled with 2% OVAto induce the reaction, and a negative control group (n=4 or 5), inwhich the mice were similarly inhaled with physiological saline. After24 hours, alveoli in the lungs of the test animals were washed withphysiological saline, and the total infiltrated white blood cells (WBC)were counted. TABLE 9 Total WBC count × Test compound 10E5/ml/mouseWithout immunization 100 Physiological saline 400 Example 1 300 Example2 200 Example 7 400 Example 10 150 Example 12 100

In addition to the compounds mentioned in the table, decrease ofinfiltrated white blood cell number was also observed when the compoundof Example 106 was used, which falls within the compound of the presentinvention.

Thus, it was confirmed that the compounds of the present invention wereuseful as medicaments for prophylactic and/or therapeutic treatment ofdiseases relating to cell migration.

Further, no abnormality was observed in the test animals (mice) afteroral administration of 30 mg/kg of the compounds for 5 consecutive days,which revealed that they were safe compounds.

Test Example 7

Action on Increase of Intracellular Calcium Concentration

According to the method described in Test Example 1, a neutrophilcontaining fraction was prepared. Fura2-AM (Sigma) at a finalconcentration of 3 μM was added to the human neutrophil fraction and themixture was incubated at 37° C. for 1 hour. After centrifugation (250 gfor 5 minutes), the supernatant was discarded, and the neutrophils wereresuspended in Hanks' Balanced Salt Solution (HBSS-, Gibco) to prepare acell suspension (8×10⁶/ml) for measurement of intracellular calciumconcentration. The cell suspension for measurement of intracellularcalcium concentration was left stand at room temperature for 30 minutes.Then, 490 μl of the cell suspension for measurement of intracellularcalcium concentration was placed in a cuvette, 10 μl of calcium chloridesolution at a final concentration of 1 μM was added to it and thecuvette was set in an intracellular calcium concentration analyzer(CAF110, Nippon Bunko). fMLP (Sigma) solution at a final concentrationof 1 μM was added to the cell suspension, and F340 and F380, which arefluorescence intensity at 340 nm and 380 nm, respectively, were measuredto obtain an R value (F340/F380) as an index of the intracellularcalcium concentration. A test compound (1 μM) was added 3 minutes beforethe addition of fMLP, and the action on the intracellular calciumconcentration was observed. The ratios of the maximum R value obtainedwith addition of each test compound, based on the maximum R valueobtained without addition of test compound and taken as 100%, are shownin Table 10 mentioned below.

It was revealed that the compounds of the present invention had almostno effect on the increase of the intracellular calcium concentrationcaused by the fMLP stimulation. TABLE 10 Maximum R value Test compound(%) None 100 Example 1 98 Example 2 99 Example 5 98 Example 7 101Example 10 99 Example 8 99 Example 20 100

Test Example 7

Action on Myosin Light Chain Phosphorylation Enzyme (MLCK) Activity

A myosin light chain phosphorylation enzyme (MLCK) was purified fromchicken gizzard smooth muscle by a conventional method (Yoshida, M., etal., J. Biochem., 99, 1027-1036 (1986)). The myosin regulatory lightchain as a substrate was purified from the chicken gizzard smooth muscleby a conventional method (Grand, R. J., et al., Biochem. J., 211,267-272 (1983)). The MLCK activity was measured by ELISA using pLC1described in Test Example 1 (Sakurada, K., et al., J. Biochem., 115,18-21 (1994)). The myosin regulatory light chain was diluted inphosphate-buffered saline (PBS, Sigma) to a concentration of 5.0 g/ml,added to 96-well Immunoplate (Nunc) in a volume of 100 μl per well andleft stand overnight at 4° C. Each well was washed with PBS, and 25 mMTris/HCl buffer containing 100 μM ATP, 3 mM MgCl₂, 1 mM CaCl₂, 100 ng/mlof calmodulin (Sigma) and 100 ng/ml of MLCK (pH 7.4, Buffer A) was addedto each well and incubated at 30° C. for 10 minutes. In a volume of 100μl each of 20% aqueous phosphoric acid solution was added to each wellto terminate the enzymatic reaction. Each well was washed with 25 mMTris/HCl buffer (TTBS) containing 0.1% Tween 20, and then 100 μl each ofpLC1 described in Test Example 1 was added to each well and incubated atroom temperature for 90 minutes.

Each well was washed with TTBS, and then 100 μl of the HRP-labeledrabbit anti-mouse IgG antibodies (Bio-Rad) were added to each well andincubated at room temperature for 90 minutes. Each well was washed withTTBS, and then 25 mM citrate buffer (pH 5.0) containingorthophenylenediamine (Sigma) as a substrate of HRP and aqueous hydrogenperoxide (0.03%) was added in a volume of 100 μl per well and incubatedat room temperature for 5 minutes. 50 μl of 4 N sulfuric acid was addedto each well to terminate the reaction, and then absorbance was measuredby using an immunoplate reader (Bio-Rad). The MLCK activity inhibitionratio was calculated by adding the test compound to Buffer A at variousconcentrations to obtain a compound concentration providing aninhibition ratio of 50% as IC₅₀. The results are as shown in Table 11mentioned below.

It was revealed that the compounds of the present invention had almostno inhibitory effect on MLCK. TABLE 11 Myosin light chainphosphorylation enzyme inhibitory action Test compound IC₅₀(μM) Example1 >50 Example 2 >50 Example 7 >50 Example 10 >30 Example 8 >50 Example20 >100

In addition to the compounds mentioned in the table, each of thecompounds of Examples 27, 29, 104, 106, 112, 120, 128, 130, 141 and 144also did not inhibit MLCK.

Industrial Applicability

The compounds of the present invention represented by the formula (1)have an inhibitory action on phosphorylation of myosin regulatory lightchain, and are useful as active ingredients of medicaments forprophylactic and/or therapeutic treatment of, for example, diseasesrelating to contraction of various cells, diseases relating tomorphological change of various cells, diseases relating to migration ofvarious cells, diseases relating to release of various cells, diseasesrelating to aggregation of various cells, diseases relating to apoptosisof various cells, and/or diseases relating to abnormality of geneexpression in various cells.

1. A compound represented by the following formula (1) or a saltthereof:

wherein R¹ represents hydrogen atom, a halogen atom, hydroxyl group,amino group, or a C₁₋₆ alkoxyl group; R² represents hydrogen atom, ahalogen atom, a C₁₋₆ alkyl group, —(C₂₋₃ alkylene)O(G¹), —(C₂₋₃alkylene)CO₂(G¹), —N(G²)(G³), —O(C₂₋₃ alkylene)O(G¹), —NH(C₂₋₃alkylene)O(G¹), —NH(C₂₋₃ alkylene)N(G²)(G³), a C₂₋₃ alkenyl group, aC₂₋₃ alkynyl group, a C₁₋₆ alkoxyl group, —(C₂₋₃ alkylene)SO₂(C₁₋₆alkyl), —S(O)_(p)(C₁₋₆ alkyl), —O(C₂₋₃ alkylene)SO₂(C₁₋₆ alkyl), orcyano group; G¹, G², and G³ independently represent hydrogen atom, or aC₁₋₆ alkyl group; p represents an integer of from 0 to 2; R³ representsa group represented by the following formula (1-1), formula (1-2), orformula (1-3);

wherein (i) when R³ represents a group represented by the formula (1-1):X represents propylene group, butylene group, —C(A⁵)(A⁵¹)—,—C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond; A¹¹, A²¹, A⁵¹, and A⁶¹independently represent hydrogen atom, or a C₁₋₆ alkyl group; A³¹represents a C₁₋₆ alkyl group substituted with hydroxyl group, orhydrogen atom; and groups in each of one or more combinations selectedfrom the group consisting of combinations of A³ and A², A³ and A¹, A³and A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ andA⁶, and A⁵ and A⁶ bind to each other to form a 5- or 6-membered ring,provided that a group or groups among A¹, A², A³, A⁵, and A⁶ notinvolved in the ring formation independently represent hydrogen atom, ora C₁₋₆ alkyl group; (ii) when R³ represents a group represented by theformula (1-2): X represents propylene group, butylene group,—C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—, or a single bond; A¹¹, A²¹, A⁵¹,and A⁶¹ independently represent hydrogen atom, or a C₁₋₆ alkyl group;A³¹ represents a C₁₋₆ alkyl group substituted with hydroxyl group, orhydrogen atom; R⁴ represents hydrogen atom, or a C₁₋₆ alkyl group; andA¹, A², A³, A⁵, and A⁶ independently represent hydrogen atom, or a C₁₋₆alkyl group; or groups in each of one or more combinations selected fromthe group consisting of combinations of A³ and A², A³ and A¹, A³ and A⁵,A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ and A⁶, and A⁵and A⁶ may bind to each other to form a 5- or 6-membered ring; and (iii)when R³ represents a group represented by the formula (1-3): Yrepresents a C₂₋₆ alkylene group, a C₂₋₆ alkylene group substituted witha C₁₋₆ alkyl group, a C₂₋₆ alkylene group substituted with phenyl group,a C₂₋₆ alkylene group substituted with benzyl group, —(C₁₋₆alkylene)phenylene(C₁₋₆ alkylene)—, 1,2-cyclohexylene group, or1,3-cyclohexylene group; A⁴ represents hydrogen atom, or a C₁₋₆ alkylgroup, or may binds to any one of carbon atoms of the alkylene moiety ofY to form a 4- to 7-membered ring; R⁵ represents —(C₂₋₆alkylene)(cycloalkyl), —(C₂₋₆ alkylene)(aryl), —(C₂₋₆alkylene)(heteroaryl), —(C₂₋₆ alkylene)S(O)_(q)(cycloalkyl), —(C₂₋₆alkylene)S(O)_(q)(aryl), —(C₂₋₆ alkylene)S(O)_(q)(heteroaryl), —(C₂₋₆alkylene)N(G⁶)(cycloalkyl), —(C₂₋₆ alkylene)N(G⁶)(aryl), —(C₂₋₆alkylene)N(G⁶)(heteroaryl), —(C₂₋₆ alkylene)CON(G⁶)(cycloalkyl), —(C₂₋₆alkylene)CON(G⁶)(aryl), or —(C₂₋₆ alkylene)CON(G⁶)(heteroaryl); G⁶represents hydrogen atom, or a C₁₋₆ alkyl group; q represents an integerof from 0 to 2; said “aryl” is a phenyl group which may be substitutedwith one or more substituents selected from the group consisting of ahalogen atom, a C₁₋₆ alkyl group, CF₃ group, a C₁₋₆ alkoxyl group, cyanogroup, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and —N(G⁹)SO₂(C₁₋₆ alkyl);G⁹ represents hydrogen atom, or a C₁₋₆ alkyl group; G⁷ and G⁸independently represents hydrogen atom, or a C₁₋₆ alkyl group, or—N(G⁷)(G⁸) in said “aryl” as a whole may form a 4- to 7-membered ringwhich may contain oxygen atom, sulfur atom, or an N(G¹⁰) group, besidessaid nitrogen atom; G¹⁰ represents hydrogen atom, or a C₁₋₆ alkyl group;said “heteroaryl” is selected from pyranyl, pyrazinyl, dioxolyl, furyl,thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, pyrrolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, and triazolyl, and these groups mayoptionally be substituted with one or more substituents selected fromthe group consisting of a C₁₋₆ alkyl group which may be substituted witha halogen atom, and a halogen atom; and r represents an integer of from0 to
 2. 2. The compound or salt thereof according to claim 1, wherein R³is a group represented by the formula (1-1).
 3. The compound or saltthereof according to claim 1, wherein R³ is a group represented by aformula (1-2).
 4. The compound or salt thereof according to claim 1 or3, wherein R³ is a group represented by a formula (1-2); X representspropylene group, butylene group, —C(A⁵)(A⁵¹)—, —C(A⁵)(A⁵¹)—C(A⁶)(A⁶l)—,or a single bond; A¹¹, A²¹, A⁵¹, and A⁶¹ independently representhydrogen atom, or a C₁₋₆ alkyl group; A³¹ is a C₁₋₆ alkyl groupsubstituted with hydroxyl group, or hydrogen atom; R⁴ is hydrogen atom,or a C₁₋₆ alkyl group; and groups in each of one or more combinationsselected from the group consisting of combinations of A³ and A², A³ andA¹, A³ and A^(5,) A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵,A¹ and A⁶, and A⁵ and A⁶ bind to each other to form a 5- or 6-memberedring (provided that among A¹, A², A³, A⁵, and A⁶, the group or groupsnot involved in the ring formation independently represent hydrogenatom, or a C₁₋₆ alkyl group).
 5. The compound or salt thereof accordingto any one of claims 1 to 4, wherein the ring formed by groups in eachof one or more combinations selected from the group consisting ofcombinations of A³ and A², A³ and A¹, A³ and A⁵, A³ and A⁶, A² and A¹,A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ and A⁶, and A5 and A⁶ binding toeach other is (i) a 6-membered ring, (ii) a ring consisting of carbonatoms, or when the ring contains a nitrogen atom to which A³ binds, aring consisting of carbon atoms except for the nitrogen atom, or (iii) asaturated ring.
 6. The compound or salt thereof according to any one ofclaims 1 to 5, wherein X is —C(A⁵)(A⁵¹)—, or —C(A⁵)(A⁵¹)—C(A⁶)(A⁶¹)—. 7.The compound or salt thereof according to any one of claims 1, 2, 5 and6, wherein R³ is a group represented by the following formula (1-1-4) orformula (1-1-7).


8. The compound or salt thereof according to any one of claims 1 and 3to 6, wherein R³ is a group represented by the following formula (1-2-4)or formula (1-2-7);


9. The compound or salt thereof according to any one of claims 1 to 8,wherein A³¹ is hydrogen atom.
 10. The compound or salt thereof accordingto any one of claims 1 to 8, wherein A³¹ is a C₁₋₆ alkyl groupsubstituted with hydroxyl group.
 11. The compound or salt thereofaccording to any one of claims 1, 3 to 6, and 8 to 10, wherein R⁴ ishydrogen atom.
 12. The compound or salt thereof according to claim 1,wherein R³ is a group represented by a formula (1-3).
 13. The compoundor salt thereof according to claim 1 or 12, wherein Y is a C₂₋₄alkylene.
 14. The compound or salt thereof according to any one ofclaims 1, 12 and 13, wherein R⁵ is —(C₂₋₄ alkylene)(aryl), —(C₂₋₄alkylene)(thienyl), —(C₂₋₄ alkylene)SO₂(aryl) or —(C₂₋₄alkylene)SO₂(thienyl), where the aryl is a phenyl group which may besubstituted with one or more substituents selected from the groupconsisting a halogen atom, a C₁₋₆ alkyl group, CF₃ group, a C₁₋₆ alkoxylgroup, cyano group, —N(G⁷)(G⁸), —CO₂(G⁹), —S(O)_(r)(G⁹), and—N(G⁹)SO₂(C₁₋₆ alkyl), where G⁹ is hydrogen atom, or a C₁₋₆ alkyl group,G⁷ and G⁸ independently represent hydrogen atom, or a C₁₋₆ alkyl group,and r is an integer of 0 to
 2. 15. The compound or salt thereofaccording to any one of claims 1 to 14, wherein R¹ is hydrogen atom,hydroxyl group, or amino group.
 16. The compound or salt thereofaccording to any one of claims 1 to 15, wherein R² is hydrogen atom, aC₁₋₆ alkyl group, a C₂₋₃ alkenyl group, a halogen atom, a —(C₂₋₃alkylene)O(G¹)13 , —S(O)_(p)(C₁₋₆ alkyl), or cyano group.
 17. Thecompound or salt thereof according to any one of claims 1 to 16, whereinR² is a C₁₋₆ alkyl group, or cyano group.
 18. The compound or saltthereof according to any one of claims 1 to 16, wherein R¹ is hydrogenatom, hydroxyl group, or amino group, and R² is a C₁₋₆ alkyl group,—(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, —S(O)_(p)(C₁₋₆ alkyl), orcyano group.
 19. The compound or salt thereof according to any one ofclaims 1, 2, 5 to 7, 9, 10, 15, 16, and 18, wherein R¹ is hydrogen atom,hydroxyl group, or amino group, R² is a C₁₋₆ alkyl group, a C₂₋₃ alkenylgroup, or cyano group, and R³ is a group represented by the formula(1-1-4) or formula (1-1-7).
 20. The compound or salt thereof accordingto any one of claims 1, 3 to 6, 8 to 11, 15, 16, and 18, wherein R¹ ishydrogen atom, hydroxyl group, or amino group, R² is a C₁₋₆ alkyl group,—(C₂₋₃ alkylene)O(G¹), a C₂₋₃ alkenyl group, or —S(O)_(p)(C₁₋₆ alkyl),R³ is a group represented by the formula (1-2-4) or formula (1-2-7), andR⁴ is hydrogen atom.
 21. The compound or salt thereof according to anyone of claims 1, 3 to 6, 8 to 11, 15, 16, 18, and 20, wherein R¹ ishydrogen atom, hydroxyl group, or amino group, R² is a C₁₋₆ alkyl group,or a C₂₋₃ alkenyl group, R³ is a group represented by the formula(1-2-4) or formula (1-2-7), and R⁴ is hydrogen atom.
 22. The compound orsalt thereof according to any one of claims 1, 12 to 16, and 18, whereinR³ is a group represented by the formula (1-3), R¹ is hydrogen atom,hydroxyl group, or amino group, R² is hydrogen atom, or a C₁₋₆ alkylgroup, and R⁵ is 3-phenylpropyl, 2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl,or 2-(phenylsulfonyl).
 23. The compound or salt thereof according toclaim 1, wherein the compound of the formula (1) is selected from thegroup consisting of 4-[(4-methyl-5-isoquinolyl)oxy]piperidine;4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;4-[(4-cyano-5-isoquinolyl)oxy]piperidine;trans-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine;trans-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine;trans-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine;cis-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine;cis-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine; andcis-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine.
 24. The compound orsalt thereof according to claim 1, wherein the compound of the formula(1) is selected from the group consisting of1-(2-hydroxyethyl)-4-[(4-methyl-5-isoquinolyl)oxy]piperidine;1-(2-hydroxyethyl)-4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;1-(2-hydroxyethyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine;trans-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;trans-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;andcis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane.25. The compound or salt thereof according to claim 1, wherein thecompound of the formula (1) is selected from the group consisting of1-(3-hydroxypropyl)-4-[(4-methyl-5-isoquinolyl)oxy]piperidine;1-(3-hydroxypropyl)-4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;1-(3-hydroxypropyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine;trans-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;trans-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;andcis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane.26. The compound or salt thereof according to claim 1, wherein thecompound of the formula (1) is selected from the group consisting of4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]piperidine;4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]piperidine;trans-4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]cyclohexylamine;trans-4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]cyclohexylamine;cis-4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]cyclohexylamine; andcis-4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]cyclohexylamine.
 27. Thecompound or salt thereof according to claim 1, wherein the compound ofthe formula (1) is selected from the group consisting of4-[(4-methyl-5-isoquinolyl)amino]piperidine;4-[(4-ethyl-5-isoquinolyl)amino]piperidine;4-[(4-vinyl-5-isoquinolyl)amino]piperidine;trans-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;trans-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine;trans-N-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediamine;cis-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;cis-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine; andcis-N-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediamine.
 28. The compoundor salt thereof according to claim 1, wherein the compound of theformula (1) is selected from the group consisting of1-(2-hydroxyethyl)-4-(4-methyl-5-isoquinolyl)aminopiperidine;1-(2-hydroxyethyl)-4-(4-ethyl-5-isoquinolyl)aminopiperidine;1-(2-hydroxyethyl)-4-(4-vinyl-5-isoquinolyl)aminopiperidine;1-(3-hydroxypropyl)-4-(4-methyl-5-isoquinolyl)aminopiperidine;1-(3-hydroxypropyl)-4-(4-ethyl-5-isoquinolyl)aminopiperidine;1-(3-hydroxypropyl)-4-(4-vinyl-5-isoquinolyl)aminopiperidine;trans-N-(4-methyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;trans-N-(4-ethyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;trans-N-(4-vinyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;trans-N-(4-methyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine;trans-N-(4-ethyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine;trans-N-(4-vinyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine;cis-N-(4-methyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;cis-N-(4-ethyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;cis-N-(4-vinyl-5-isoquinolyl)-N′-(2-hydroxyethyl)-1,4-cyclohexanediamine;cis-N-(4-methyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine;cis-N-(4-ethyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine;andcis-N-(4-vinyl-5-isoquinolyl)-N′-(3-hydroxypropyl)-1,4-cyclohexanediamine.29. The compound or salt thereof according to claim 1, wherein thecompound of the formula (1) is selected from the group consisting of4-(1-hydroxy-4-methyl-5-isoquinolyl)aminopiperidine;4-(1-hydroxy-4-ethyl-5-isoquinolyl)aminopiperidine;trans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;trans-N-(1-hydroxy-4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine;cis-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine; andcis-N-(1-hydroxy-4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine.
 30. Thecompound or salt thereof according to claim 1, wherein the compound ofthe formula (1) is selected from the group consisting ofN-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;andN-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine.31. The compound or salt thereof according to claim 1, wherein thecompound of the formula (1) is selected from the group consisting ofN-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;andN-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine.32. The compound or salt thereof according to claim 1, wherein thecompound of the formula (1) is selected from the group consisting ofN-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-ethylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-ethylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-ethylenediamine;N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;andN-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethyl-enediamine.33. A medicament comprising a compound represented by the formula (1) ora physiologically acceptable salt thereof.
 34. The medicament accordingto claim 33, which is used for prophylactic and/or therapeutic treatmentof glaucoma.
 35. The medicament according to claim 33, which is used forprophylactic and/or therapeutic treatment of bronchial asthma and/orchronic obstructive pulmonary disease.
 36. An inhibitor of thephosphorylation of myosin regulatory light chain, which comprises acompound represented by the formula (1) or a salt thereof according toclaim
 1. 37. An inhibitor of the Rho/Rho kinase pathway, which comprisesa compound represented by the formula (1) or a salt thereof according toclaim 1.